{"gene":"GRPEL1","run_date":"2026-04-28T18:06:53","timeline":{"discoveries":[{"year":1994,"finding":"Mge1p (yeast mitochondrial GrpE/GRPEL1 ortholog) was identified as the first eukaryotic GrpE-related protein, shown to be an essential nuclear-encoded soluble protein of the mitochondrial matrix that cooperates with mitochondrial Hsp70 (mt-Hsp70) in protein translocation into mitochondria; cells with reduced Mge1p accumulate mitochondrial precursor proteins.","method":"Yeast genetics, subcellular fractionation, precursor import assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — foundational ortholog study with genetic depletion, import assays, and functional demonstration; replicated by multiple independent labs","pmids":["8022808"],"is_preprint":false},{"year":1994,"finding":"Yeast GrpEp (GRPEL1 ortholog) is made as a precursor that is cleaved upon import into mitochondria, physically interacts with mitochondrial Hsp70 (mt-Hsp70) via ATP-sensitive binding, is essential for viability, and functions analogously to bacterial GrpE with DnaK.","method":"Affinity purification with His-tagged mt-Hsp70, ATP dissociation assay, gene cloning, microsequencing, mitochondrial import assay","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1-2 — biochemical reconstitution, affinity purification, ATP-dependent dissociation, microsequencing validation; independent replication","pmids":["8168496"],"is_preprint":false},{"year":1994,"finding":"Yeast Yge1p (GRPEL1 ortholog) localizes to the mitochondrial matrix as a soluble protein, physically interacts with mitochondrial Hsp70 (Ssc1p) by co-immunoprecipitation, is essential for cell viability, and is required for protein import into mitochondria (depletion causes precursor accumulation of F1-ATPase β subunit).","method":"Co-immunoprecipitation, subcellular fractionation, in vivo precursor accumulation assay","journal":"FEBS letters","confidence":"High","confidence_rationale":"Tier 2 — co-IP plus functional import assay, ortholog confirmed in independent lab","pmids":["8112465","8166717"],"is_preprint":false},{"year":1994,"finding":"Mitochondrial GrpE (MGE, GRPEL1 ortholog) in Neurospora crassa and S. cerevisiae is quantitatively bound to matrix mt-Hsp70, released by Mg-ATP (but not non-hydrolyzable analogs or high salt), and co-precipitates with preproteins in transit across mitochondrial membranes, demonstrating that mt-Hsp70 and MGE cooperate in membrane translocation.","method":"Immunoprecipitation with anti-MGE and anti-mt-Hsp70 antibodies, ATP-dependent dissociation assay, import intermediate trapping","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 — reciprocal immunoprecipitation, ATP-dependent release, import intermediate co-precipitation; cross-species validation","pmids":["7935381"],"is_preprint":false},{"year":1995,"finding":"Yeast Mge1p (GRPEL1 ortholog) conditional mutants impair mt-Hsp70 binding to incoming precursor proteins, reduce nucleotide-dependent dissociation of mt-Hsp70 from MIM44, and cause increased protein aggregation and incomplete folding of newly imported proteins; Mge1p promotes the progress of the Hsp70 reaction cycle for protein import and folding.","method":"Temperature-sensitive mge1 mutants, mitochondrial import kinetics assay, mt-Hsp70–MIM44 interaction assay, protein aggregation assay","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 — conditional mutant with multiple functional readouts (import kinetics, Hsp70-MIM44 interaction, folding, aggregation); mechanistically detailed","pmids":["7628446"],"is_preprint":false},{"year":1995,"finding":"Yeast Mge1p (GRPEL1 ortholog) mutant mitochondria show defective mt-Hsp70 binding to translocating precursors and impaired maturation (retarded second proteolytic processing); wild-type Mge1p promotes mt-Hsp70 cycling by modulating nucleotide-dependent substrate binding.","method":"Conditional mge1 mutants, preprotein import assay, proteolytic processing assay, mt-Hsp70–preprotein interaction measurements","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 — genetic mutant combined with biochemical import and processing assays; independent confirmation of Mge1p mechanism","pmids":["8524277"],"is_preprint":false},{"year":1997,"finding":"Yeast Mge1p (GRPEL1 ortholog) stimulates ATP hydrolysis by mt-Hsp70 approximately 2-fold and promotes the ATPase cycle by increasing the rate of ADP release rather than directly affecting phosphate release; inorganic phosphate inhibits ATP hydrolysis by preventing ADP release, and Mge1p relieves this phosphate inhibition.","method":"In vitro ATPase assay with purified recombinant mt-Hsp70 and Mge1p, phosphate inhibition experiments","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 — in vitro biochemical reconstitution with purified components; mechanistic dissection of nucleotide exchange","pmids":["9237899"],"is_preprint":false},{"year":1996,"finding":"Rat mitochondrial GrpE (mt-GrpE, GRPEL1 ortholog) is a 21 kDa nuclear-encoded protein present exclusively in the mitochondrial fraction; its transcript is expressed in most organs; unlike other mitochondrial chaperones, mt-GrpE levels are only marginally increased by heat shock or proline analog stress, suggesting constitutive expression.","method":"cDNA cloning, Western blotting of subcellular fractions, Northern blotting across tissues, stress induction experiments","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 — biochemical fractionation with localization, but primary findings are expression-level; functional characterization limited","pmids":["8914984"],"is_preprint":false},{"year":1998,"finding":"Two mammalian mitochondrial GrpE-like proteins (mt-GrpE#1/GRPEL1 and mt-GrpE#2/GRPEL2) were identified; both bind specifically to E. coli DnaK in an ATP-dissociable manner, interact with mammalian mt-Hsp70, and stimulate its ATPase activity; they share ~47% amino acid identity and differ in 3'-UTR destabilization elements, suggesting different post-transcriptional regulation.","method":"DnaK affinity binding assay, ATP dissociation, ATPase stimulation assay with purified mammalian mt-Hsp70, cDNA cloning, sequence analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — biochemical binding assays, ATPase stimulation, multi-method characterization of both paralogs in the same study","pmids":["9694873"],"is_preprint":false},{"year":2001,"finding":"Human HMGE (GRPEL1 ortholog) was identified as a mitochondrial protein that co-purifies with E. coli DnaK and is released by Mg-ATP; it also binds cytosolic Hsc70 and the DnaJ-domain protein HSJ1b; HMGE inhibits HSJ1b-enhanced Hsc70 ATPase activity and may interact directly with DnaJ proteins, representing the first reported DnaJ–GrpE direct interaction.","method":"GST pulldown with DnaK, ATP dissociation assay, subcellular fractionation, immunocytochemistry, co-immunoprecipitation with Hsc70 and HSJ1b, ATPase inhibition assay","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 2-3 — multiple biochemical assays but single lab; interaction with cytosolic Hsc70 is unexpected and awaits independent confirmation","pmids":["11311562"],"is_preprint":false},{"year":2003,"finding":"Free human mitochondrial GrpE (GRPEL1) forms a symmetric dimer in solution, with an elongated cruciform shape as determined by analytical ultracentrifugation and small-angle X-ray scattering; the symmetric dimer becomes asymmetric upon DnaK binding, suggesting a conformational change upon complex formation.","method":"Circular dichroism, differential scanning calorimetry, analytical ultracentrifugation, small-angle X-ray scattering (SAXS)","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — multiple biophysical methods (SAXS, AUC, CD, DSC) providing convergent structural evidence","pmids":["12840016"],"is_preprint":false},{"year":2017,"finding":"Human GrpEL1 and GrpEL2 both associate with mtHsp70 as a hetero-oligomeric subcomplex in human cells; this hetero-oligomeric complex formation is critical for conferring stability to both NEFs; GrpEL1 and GrpEL2 together regulate mtHsp70-dependent import of preproteins and biogenesis of Fe-S clusters; GrpEL2 has evolved as a stress-resistance protein, while GrpEL1 functions as a stress modulator.","method":"Co-immunoprecipitation, RNAi knockdown, mitochondrial preprotein import assay, Fe-S cluster biogenesis assay, stability assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (co-IP, functional import assays, Fe-S biogenesis, stability), direct study of human GrpEL1 and GrpEL2","pmids":["28848044"],"is_preprint":false},{"year":2020,"finding":"Dengue virus NS3 protease is imported into the mitochondrial matrix via an intrinsic mitochondrial transport signal and cleaves GrpEL1 at sites KR81A and QR92S; GrpEL1 levels are reduced in NS3-expressing cells, NS3-helicase-expressing cells, virus-infected cells, and severe dengue clinical samples, identifying GrpEL1 as a substrate of dengue NS3 protease.","method":"In silico MTS prediction, transient transfection, mitochondrial import assay, purified component cleavage assay, site mapping, Western blotting in clinical samples","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 1-2 — in vitro cleavage with purified components, site mapping by mutagenesis, validated ex vivo in virus-infected cells and clinical samples","pmids":["32581108"],"is_preprint":false},{"year":2022,"finding":"After subarachnoid hemorrhage (SAH), the GrpEL1–mtHsp70 complex is reduced in neurons; overexpression of GrpEL1 increases GrpEL1–mtHsp70 complex formation (by co-immunoprecipitation), decreases protein aggresomes, improves mitochondrial membrane potential, increases ATP content, and decreases cleaved Caspase-9, demonstrating that the GrpEL1–mtHsp70 interaction is essential for mitochondrial protein quality control and neuronal survival after SAH.","method":"Co-immunoprecipitation, aggresome staining, JC-1 mitochondrial membrane potential assay, ATP measurement, Western blot (cleaved Caspase-9), GrpEL1 overexpression in primary neurons","journal":"Brain research bulletin","confidence":"Medium","confidence_rationale":"Tier 2-3 — co-IP plus functional readouts (aggresomes, membrane potential, ATP, apoptosis) in cellular model; single lab, disease-specific context","pmids":["35093469"],"is_preprint":false},{"year":2020,"finding":"GRPEL1 was identified as a physical interactor of SARS-CoV-2 proteins by affinity-purification mass spectrometry in human cells, placing it within the host-virus protein interaction network.","method":"Affinity-purification mass spectrometry (AP-MS) of tagged SARS-CoV-2 proteins in HEK293T cells","journal":"Nature","confidence":"Low","confidence_rationale":"Tier 3 — single AP-MS dataset; interaction identified but not mechanistically validated for GRPEL1 specifically","pmids":["32353859"],"is_preprint":false}],"current_model":"GRPEL1 is a nuclear-encoded mitochondrial matrix protein that forms a hetero-oligomeric complex with its paralog GRPEL2, functions as a nucleotide exchange factor (NEF) for mitochondrial Hsp70 (mtHsp70) by promoting ADP release and ATP rebinding, and thereby drives mtHsp70-dependent preprotein import, Fe-S cluster biogenesis, and mitochondrial protein quality control; it is cleaved and inactivated by dengue virus NS3 protease at sites KR81A/QR92S, and its reduced interaction with mtHsp70 leads to accumulation of protein aggresomes and mitochondrial dysfunction."},"narrative":{"teleology":[{"year":1994,"claim":"Identification of a mitochondrial GrpE homolog answered whether eukaryotic mitochondria possess a dedicated Hsp70 nucleotide exchange factor; yeast Mge1p was shown to be an essential, nuclear-encoded, matrix-localized protein required for preprotein import.","evidence":"Yeast genetics, subcellular fractionation, import assays, co-immunoprecipitation, and ATP-dependent dissociation from mt-Hsp70 across S. cerevisiae and N. crassa","pmids":["8022808","8168496","8112465","7935381"],"confidence":"High","gaps":["Mammalian ortholog not yet characterized","Mechanism of nucleotide exchange not dissected at the kinetic level","Structural basis of the GrpE–Hsp70 interaction unknown"]},{"year":1995,"claim":"Conditional mutant studies resolved that Mge1p promotes mt-Hsp70 cycling on translocating substrates by facilitating nucleotide-dependent substrate release, and that loss of this cycling leads to protein aggregation and incomplete folding inside mitochondria.","evidence":"Temperature-sensitive mge1 mutants with measurements of mt-Hsp70–preprotein binding, Hsp70–MIM44 dissociation, and protein aggregation in yeast mitochondria","pmids":["7628446","8524277"],"confidence":"High","gaps":["Whether Mge1p directly contacts the translocon or acts solely through Hsp70 cycling was unresolved","Quantitative rate constants for ADP release not yet measured"]},{"year":1997,"claim":"Reconstitution with purified components demonstrated that Mge1p stimulates mt-Hsp70 ATPase activity by accelerating ADP release rather than phosphate release, defining its precise biochemical step in the Hsp70 catalytic cycle.","evidence":"In vitro ATPase assay with purified recombinant mt-Hsp70 and Mge1p, phosphate inhibition experiments","pmids":["9237899"],"confidence":"High","gaps":["Whether the mechanism is conserved in mammalian GRPEL1 was not directly tested","Structural basis for ADP release stimulation unknown"]},{"year":1998,"claim":"Discovery that mammals encode two mitochondrial GrpE paralogs (GRPEL1 and GRPEL2), both capable of binding mt-Hsp70 and stimulating its ATPase activity, raised the question of why two NEFs are maintained.","evidence":"DnaK affinity binding, ATP dissociation assay, ATPase stimulation with purified mammalian mt-Hsp70, cDNA cloning","pmids":["9694873"],"confidence":"High","gaps":["Functional specialization of GRPEL1 vs. GRPEL2 not addressed","Whether the two paralogs form a heterocomplex was unknown"]},{"year":2003,"claim":"Biophysical characterization established that free GRPEL1 forms an elongated symmetric homodimer that undergoes conformational rearrangement to an asymmetric state upon DnaK/Hsp70 binding, providing the first structural insight into the mammalian NEF.","evidence":"Analytical ultracentrifugation, SAXS, circular dichroism, and differential scanning calorimetry of human GRPEL1","pmids":["12840016"],"confidence":"High","gaps":["High-resolution atomic structure not available","Whether GRPEL1 functions as a heterodimer with GRPEL2 in vivo was unknown"]},{"year":2017,"claim":"The discovery that GRPEL1 and GRPEL2 form a hetero-oligomeric complex in human cells resolved the question of paralog specialization: the heterodimer is required for mutual stability and jointly regulates mtHsp70-dependent preprotein import and Fe-S cluster biogenesis, with GRPEL2 providing stress resistance and GRPEL1 acting as a stress modulator.","evidence":"Co-immunoprecipitation, RNAi knockdown, mitochondrial import and Fe-S biogenesis assays in human cells","pmids":["28848044"],"confidence":"High","gaps":["Stoichiometry and architecture of the heterodimer remain undefined","Whether heterodimer formation is regulated under stress conditions is unclear"]},{"year":2020,"claim":"Dengue virus NS3 protease was shown to target GRPEL1 for proteolytic cleavage inside the mitochondrial matrix at two defined sites, establishing GRPEL1 destruction as a viral strategy to disrupt mitochondrial protein homeostasis.","evidence":"In vitro cleavage with purified NS3 protease, cleavage-site mutagenesis, mitochondrial import of NS3, Western blotting in virus-infected cells and severe dengue clinical samples","pmids":["32581108"],"confidence":"High","gaps":["Whether GRPEL2 is also cleaved by NS3 was not tested","Downstream consequences of GRPEL1 cleavage on Fe-S biogenesis and import in infected cells not measured"]},{"year":2022,"claim":"Functional rescue experiments in neurons after subarachnoid hemorrhage demonstrated that loss of the GRPEL1–mtHsp70 complex leads to protein aggresome accumulation, mitochondrial depolarization, and caspase-9-dependent apoptosis, directly linking GRPEL1's NEF function to mitochondrial protein quality control and cell survival.","evidence":"GrpEL1 overexpression in primary neurons, co-IP, aggresome staining, JC-1 assay, ATP measurement, cleaved caspase-9 Western blot","pmids":["35093469"],"confidence":"Medium","gaps":["Findings from a single lab in one disease model; independent replication needed","Whether GRPEL2 compensates for GRPEL1 loss in this context was not addressed","Causal link between specific GRPEL1–mtHsp70 substrates and aggresome formation not established"]},{"year":null,"claim":"Key unresolved questions include the high-resolution structure of the human GRPEL1–GRPEL2–mtHsp70 ternary complex, the mechanism governing heterodimer vs. homodimer assembly, and whether GRPEL1 plays roles in additional mitochondrial pathways beyond import and Fe-S cluster biogenesis.","evidence":"","pmids":[],"confidence":"High","gaps":["No high-resolution structure of the human GRPEL1–mtHsp70 complex exists","Regulation of GRPEL1–GRPEL2 heterodimer assembly is unexplored","Complete substrate repertoire of GRPEL1-dependent mtHsp70 activity is unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[6,8,11]},{"term_id":"GO:0044183","term_label":"protein folding chaperone","supporting_discovery_ids":[4,5,11,13]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[0,1,2,3,7,8,11,12]}],"pathway":[{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[0,2,4,5,11]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[4,5,11,13]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[12]}],"complexes":["GRPEL1–GRPEL2 hetero-oligomeric NEF complex","mtHsp70–GRPEL1/GRPEL2 chaperone complex"],"partners":["HSPA9","GRPEL2"],"other_free_text":[]},"mechanistic_narrative":"GRPEL1 is a nuclear-encoded mitochondrial matrix nucleotide exchange factor (NEF) that drives the ATPase cycle of mitochondrial Hsp70 (mtHsp70) by accelerating ADP release, thereby enabling mtHsp70-dependent preprotein import, iron-sulfur cluster biogenesis, and mitochondrial protein quality control [PMID:8022808, PMID:9237899, PMID:28848044]. GRPEL1 forms a homodimer in its free state and assembles into a hetero-oligomeric complex with its paralog GRPEL2, a partnership that confers mutual stability and is required for full NEF activity toward mtHsp70 [PMID:12840016, PMID:28848044]. Loss of GrpEL1–mtHsp70 interaction leads to accumulation of protein aggresomes, impaired mitochondrial membrane potential, and apoptotic signaling [PMID:35093469]. Dengue virus NS3 protease enters the mitochondrial matrix and cleaves GRPEL1 at KR81↓A and QR92↓S, reducing its steady-state levels during infection and in severe dengue patient samples [PMID:32581108]."},"prefetch_data":{"uniprot":{"accession":"Q9HAV7","full_name":"GrpE protein homolog 1, mitochondrial","aliases":["HMGE","Mt-GrpE#1"],"length_aa":217,"mass_kda":24.3,"function":"Essential component of the PAM complex, a complex required for the translocation of transit peptide-containing proteins from the inner membrane into the mitochondrial matrix in an ATP-dependent manner (By similarity). Seems to control the nucleotide-dependent binding of mitochondrial HSP70 to substrate proteins (PubMed:11311562)","subcellular_location":"Mitochondrion matrix","url":"https://www.uniprot.org/uniprotkb/Q9HAV7/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/GRPEL1","classification":"Common Essential","n_dependent_lines":1190,"n_total_lines":1208,"dependency_fraction":0.9850993377483444},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/GRPEL1","total_profiled":1310},"omim":[{"mim_id":"618545","title":"GRPE-LIKE 2, MITOCHONDRIAL; GRPEL2","url":"https://www.omim.org/entry/618545"},{"mim_id":"608382","title":"DNAJ/HSP40 HOMOLOG, SUBFAMILY A, MEMBER 3; DNAJA3","url":"https://www.omim.org/entry/608382"},{"mim_id":"606173","title":"GRPE-LIKE 1, MITOCHONDRIAL; GRPEL1","url":"https://www.omim.org/entry/606173"},{"mim_id":"604572","title":"DNAJ/HSP40 HOMOLOG, SUBFAMILY B, MEMBER 1; DNAJB1","url":"https://www.omim.org/entry/604572"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Mitochondria","reliability":"Supported"},{"location":"Nucleoplasm","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/GRPEL1"},"hgnc":{"alias_symbol":["FLJ25609","GrpE","hMGE"],"prev_symbol":[]},"alphafold":{"accession":"Q9HAV7","domains":[{"cath_id":"3.90.20","chopping":"59-158","consensus_level":"medium","plddt":93.525,"start":59,"end":158},{"cath_id":"2.30.22.10","chopping":"160-217","consensus_level":"medium","plddt":92.3721,"start":160,"end":217}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9HAV7","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9HAV7-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9HAV7-F1-predicted_aligned_error_v6.png","plddt_mean":80.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=GRPEL1","jax_strain_url":"https://www.jax.org/strain/search?query=GRPEL1"},"sequence":{"accession":"Q9HAV7","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9HAV7.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9HAV7/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9HAV7"}},"corpus_meta":[{"pmid":"1826368","id":"PMC_1826368","title":"Escherichia coli DnaJ and GrpE heat shock proteins jointly stimulate ATPase activity of DnaK.","date":"1991","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/1826368","citation_count":744,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"7900997","id":"PMC_7900997","title":"DnaK, DnaJ and GrpE form a cellular chaperone machinery capable of repairing heat-induced protein damage.","date":"1993","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/7900997","citation_count":531,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"7937953","id":"PMC_7937953","title":"The ATP hydrolysis-dependent reaction cycle of the Escherichia coli Hsp70 system DnaK, DnaJ, and GrpE.","date":"1994","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/7937953","citation_count":453,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"9103205","id":"PMC_9103205","title":"Crystal structure of the nucleotide exchange factor GrpE bound to the ATPase domain of the molecular chaperone DnaK.","date":"1997","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/9103205","citation_count":410,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"9572938","id":"PMC_9572938","title":"Chaperone coexpression plasmids: differential and synergistic roles of DnaK-DnaJ-GrpE and GroEL-GroES in assisting folding of an allergen of Japanese cedar pollen, Cryj2, in Escherichia coli.","date":"1998","source":"Applied and environmental microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/9572938","citation_count":346,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"9321400","id":"PMC_9321400","title":"GrpE-like regulation of the hsc70 chaperone by the anti-apoptotic protein BAG-1.","date":"1997","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/9321400","citation_count":321,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"10497158","id":"PMC_10497158","title":"ClpB cooperates with DnaK, DnaJ, and GrpE in suppressing protein aggregation. A novel multi-chaperone system from Escherichia coli.","date":"1999","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10497158","citation_count":290,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"1534276","id":"PMC_1534276","title":"Physical interaction between heat shock proteins DnaK, DnaJ, and GrpE and the bacterial heat shock transcription factor sigma 32.","date":"1992","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/1534276","citation_count":282,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"2527744","id":"PMC_2527744","title":"Initiation of lambda DNA replication with purified host- and bacteriophage-encoded proteins: the role of the dnaK, dnaJ and grpE heat shock proteins.","date":"1989","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/2527744","citation_count":272,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"8599944","id":"PMC_8599944","title":"A cycle of binding and release of the DnaK, DnaJ and GrpE chaperones regulates activity of the Escherichia coli heat shock transcription factor sigma32.","date":"1996","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/8599944","citation_count":232,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"10377389","id":"PMC_10377389","title":"Heat-inactivated proteins are rescued by the DnaK.J-GrpE set and ClpB chaperones.","date":"1999","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/10377389","citation_count":211,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"9131990","id":"PMC_9131990","title":"GrpE accelerates nucleotide exchange of the molecular chaperone DnaK with an associative displacement mechanism.","date":"1997","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/9131990","citation_count":155,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"7836448","id":"PMC_7836448","title":"The DnaK chaperone system of Escherichia coli: quaternary structures and interactions of the DnaK and GrpE components.","date":"1995","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/7836448","citation_count":154,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"2826421","id":"PMC_2826421","title":"The grpE protein of Escherichia coli. Purification and properties.","date":"1987","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/2826421","citation_count":152,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"8022808","id":"PMC_8022808","title":"A role for a eukaryotic GrpE-related protein, Mge1p, in protein translocation.","date":"1994","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/8022808","citation_count":150,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"8168496","id":"PMC_8168496","title":"A mitochondrial homolog of bacterial GrpE interacts with mitochondrial hsp70 and is essential for viability.","date":"1994","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/8168496","citation_count":149,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"1400176","id":"PMC_1400176","title":"DnaK, DnaJ, and GrpE are required for flagellum synthesis in Escherichia coli.","date":"1992","source":"Journal of bacteriology","url":"https://pubmed.ncbi.nlm.nih.gov/1400176","citation_count":141,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"7876226","id":"PMC_7876226","title":"Modulation of the ATPase activity of the molecular chaperone DnaK by peptides and the DnaJ and GrpE heat shock proteins.","date":"1995","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/7876226","citation_count":123,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"7656024","id":"PMC_7656024","title":"A conserved loop in the ATPase domain of the DnaK chaperone is essential for stable binding of GrpE.","date":"1994","source":"Nature structural biology","url":"https://pubmed.ncbi.nlm.nih.gov/7656024","citation_count":118,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"7902351","id":"PMC_7902351","title":"Both the Escherichia coli chaperone systems, GroEL/GroES and DnaK/DnaJ/GrpE, can reactivate heat-treated RNA polymerase. Different mechanisms for the same activity.","date":"1993","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/7902351","citation_count":111,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"8606155","id":"PMC_8606155","title":"Identification of a Caulobacter crescentus operon encoding hrcA, involved in negatively regulating heat-inducible transcription, and the chaperone gene grpE.","date":"1996","source":"Journal of bacteriology","url":"https://pubmed.ncbi.nlm.nih.gov/8606155","citation_count":110,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"1577695","id":"PMC_1577695","title":"Molecular characterization of the dnaK gene region of Clostridium acetobutylicum, including grpE, dnaJ, and a new heat shock gene.","date":"1992","source":"Journal of bacteriology","url":"https://pubmed.ncbi.nlm.nih.gov/1577695","citation_count":110,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"9223639","id":"PMC_9223639","title":"The power stroke of the DnaK/DnaJ/GrpE molecular chaperone system.","date":"1997","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/9223639","citation_count":109,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"9282745","id":"PMC_9282745","title":"Transcriptional analysis of the Streptococcus mutans hrcA, grpE and dnaK genes and regulation of expression in response to heat shock and environmental acidification.","date":"1997","source":"Molecular microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/9282745","citation_count":99,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"11752390","id":"PMC_11752390","title":"The chloroplastic GrpE homolog of Chlamydomonas: two isoforms generated by differential splicing.","date":"2001","source":"The Plant cell","url":"https://pubmed.ncbi.nlm.nih.gov/11752390","citation_count":97,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"2651417","id":"PMC_2651417","title":"The heat-shock-regulated grpE gene of Escherichia coli is required for bacterial growth at all temperatures but is dispensable in certain mutant backgrounds.","date":"1989","source":"Journal of bacteriology","url":"https://pubmed.ncbi.nlm.nih.gov/2651417","citation_count":97,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"14984054","id":"PMC_14984054","title":"GrpE, a nucleotide exchange factor for DnaK.","date":"2003","source":"Cell stress & chaperones","url":"https://pubmed.ncbi.nlm.nih.gov/14984054","citation_count":93,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"2183004","id":"PMC_2183004","title":"Roles of Escherichia coli heat shock proteins DnaK, DnaJ and GrpE in mini-F plasmid replication.","date":"1990","source":"Molecular & general genetics : MGG","url":"https://pubmed.ncbi.nlm.nih.gov/2183004","citation_count":88,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"8655561","id":"PMC_8655561","title":"Involvement of the DnaK-DnaJ-GrpE chaperone team in protein secretion in Escherichia coli.","date":"1996","source":"Journal of bacteriology","url":"https://pubmed.ncbi.nlm.nih.gov/8655561","citation_count":88,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"7628446","id":"PMC_7628446","title":"The role of the GrpE homologue, Mge1p, in mediating protein import and protein folding in mitochondria.","date":"1995","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/7628446","citation_count":82,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"2424889","id":"PMC_2424889","title":"Escherichia coli grpE gene codes for heat shock protein B25.3, essential for both lambda DNA replication at all temperatures and host growth at high temperature.","date":"1986","source":"Journal of bacteriology","url":"https://pubmed.ncbi.nlm.nih.gov/2424889","citation_count":82,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"7935381","id":"PMC_7935381","title":"Mitochondrial GrpE is present in a complex with hsp70 and preproteins in transit across membranes.","date":"1994","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/7935381","citation_count":78,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"1438220","id":"PMC_1438220","title":"DnaJ, DnaK, and GrpE heat shock proteins are required in oriP1 DNA replication solely at the RepA monomerization step.","date":"1992","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/1438220","citation_count":76,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"8112465","id":"PMC_8112465","title":"YGE1 is a yeast homologue of Escherichia coli grpE and is required for maintenance of mitochondrial functions.","date":"1994","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/8112465","citation_count":75,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"2681150","id":"PMC_2681150","title":"Participation of Escherichia coli heat shock proteins DnaJ, DnaK, and GrpE in P1 plasmid replication.","date":"1989","source":"Journal of bacteriology","url":"https://pubmed.ncbi.nlm.nih.gov/2681150","citation_count":74,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"9852006","id":"PMC_9852006","title":"The Hsc66-Hsc20 chaperone system in Escherichia coli: chaperone activity and interactions with the DnaK-DnaJ-grpE system.","date":"1998","source":"Journal of bacteriology","url":"https://pubmed.ncbi.nlm.nih.gov/9852006","citation_count":74,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"9506960","id":"PMC_9506960","title":"Control of the DnaK chaperone cycle by substoichiometric concentrations of the co-chaperones DnaJ and GrpE.","date":"1998","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/9506960","citation_count":70,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"8444859","id":"PMC_8444859","title":"Initiation of lambda DNA replication. The Escherichia coli small heat shock proteins, DnaJ and GrpE, increase DnaK's affinity for the lambda P protein.","date":"1993","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/8444859","citation_count":70,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"1361234","id":"PMC_1361234","title":"Activity of the Hsp70 chaperone complex--DnaK, DnaJ, and GrpE--in initiating phage lambda DNA replication by sequestering and releasing lambda P protein.","date":"1992","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/1361234","citation_count":66,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"8524277","id":"PMC_8524277","title":"Mitochondrial GrpE modulates the function of matrix Hsp70 in translocation and maturation of preproteins.","date":"1995","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/8524277","citation_count":64,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"9657681","id":"PMC_9657681","title":"Temperature-controlled activity of DnaK-DnaJ-GrpE chaperones: protein-folding arrest and recovery during and after heat shock depends on the substrate protein and the GrpE concentration.","date":"1998","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/9657681","citation_count":63,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"15102842","id":"PMC_15102842","title":"Influence of GrpE on DnaK-substrate interactions.","date":"2004","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/15102842","citation_count":60,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"22128139","id":"PMC_22128139","title":"Recent gene duplication and subfunctionalization produced a mitochondrial GrpE, the nucleotide exchange factor of the Hsp70 complex, specialized in thermotolerance to chronic heat stress in Arabidopsis.","date":"2011","source":"Plant physiology","url":"https://pubmed.ncbi.nlm.nih.gov/22128139","citation_count":59,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"11724541","id":"PMC_11724541","title":"Folding properties of the nucleotide exchange factor GrpE from Thermus thermophilus: GrpE is a thermosensor that mediates heat shock response.","date":"2001","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/11724541","citation_count":59,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"3045760","id":"PMC_3045760","title":"Sequence analysis and transcriptional regulation of the Escherichia coli grpE gene, encoding a heat shock protein.","date":"1988","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/3045760","citation_count":59,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"2522091","id":"PMC_2522091","title":"Escherichia coli DnaK and GrpE heat shock proteins interact both in vivo and in vitro.","date":"1989","source":"Journal of bacteriology","url":"https://pubmed.ncbi.nlm.nih.gov/2522091","citation_count":58,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"16109938","id":"PMC_16109938","title":"The heat shock genes dnaK, dnaJ, and grpE are involved in regulation of putisolvin biosynthesis in Pseudomonas putida PCL1445.","date":"2005","source":"Journal of bacteriology","url":"https://pubmed.ncbi.nlm.nih.gov/16109938","citation_count":57,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"8459764","id":"PMC_8459764","title":"Isolation of dnaJ, dnaK, and grpE homologues from Borrelia burgdorferi and complementation of Escherichia coli mutants.","date":"1993","source":"Molecular microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/8459764","citation_count":53,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"8501058","id":"PMC_8501058","title":"Heat shock proteins DnaJ, DnaK, and GrpE stimulate P1 plasmid replication by promoting initiator binding to the origin.","date":"1993","source":"Journal of bacteriology","url":"https://pubmed.ncbi.nlm.nih.gov/8501058","citation_count":53,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"25451597","id":"PMC_25451597","title":"Interplay between E. coli DnaK, ClpB and GrpE during protein disaggregation.","date":"2014","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/25451597","citation_count":51,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"25487014","id":"PMC_25487014","title":"GrpE, Hsp110/Grp170, HspBP1/Sil1 and BAG domain proteins: nucleotide exchange factors for Hsp70 molecular chaperones.","date":"2015","source":"Sub-cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/25487014","citation_count":48,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"28848044","id":"PMC_28848044","title":"Regulation of mitochondrial protein import by the nucleotide exchange factors GrpEL1 and GrpEL2 in human cells.","date":"2017","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/28848044","citation_count":47,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"14731284","id":"PMC_14731284","title":"Escherichia coli Hsp31 functions as a holding chaperone that cooperates with the DnaK-DnaJ-GrpE system in the management of protein misfolding under severe stress conditions.","date":"2004","source":"Molecular microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/14731284","citation_count":47,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"22544739","id":"PMC_22544739","title":"Crystal structure of DnaK protein complexed with nucleotide exchange factor GrpE in DnaK chaperone system: insight into intermolecular communication.","date":"2012","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/22544739","citation_count":45,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"8166717","id":"PMC_8166717","title":"Yge1p, a eukaryotic Grp-E homolog, is localized in the mitochondrial matrix and interacts with mitochondrial Hsp70.","date":"1994","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/8166717","citation_count":45,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"503859","id":"PMC_503859","title":"Subnucleosome particles containing high mobility group proteins HMG-E and HMG-G originate from transcriptionally active chromatin.","date":"1979","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/503859","citation_count":44,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"8898387","id":"PMC_8898387","title":"Protein folding in the cytoplasm of Escherichia coli: requirements for the DnaK-DnaJ-GrpE and GroEL-GroES molecular chaperone machines.","date":"1996","source":"Molecular microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/8898387","citation_count":43,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"9694873","id":"PMC_9694873","title":"Evidence for the existence of distinct mammalian cytosolic, microsomal, and two mitochondrial GrpE-like proteins, the Co-chaperones of specific Hsp70 members.","date":"1998","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/9694873","citation_count":43,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"9237899","id":"PMC_9237899","title":"Role of mitochondrial GrpE and phosphate in the ATPase cycle of matrix Hsp70.","date":"1997","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/9237899","citation_count":43,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"18599817","id":"PMC_18599817","title":"The proper ratio of GrpE to DnaK is important for protein quality control by the DnaK-DnaJ-GrpE chaperone system and for cell division.","date":"2008","source":"Microbiology (Reading, England)","url":"https://pubmed.ncbi.nlm.nih.gov/18599817","citation_count":42,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"15632130","id":"PMC_15632130","title":"Dimeric trigger factor stably binds folding-competent intermediates and cooperates with the DnaK-DnaJ-GrpE chaperone system to allow refolding.","date":"2005","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/15632130","citation_count":38,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"11376662","id":"PMC_11376662","title":"Mutations in the interdomain linker region of DnaK abolish the chaperone action of the DnaK/DnaJ/GrpE system.","date":"2001","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/11376662","citation_count":38,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"8890154","id":"PMC_8890154","title":"Structure-function analysis of the Escherichia coli GrpE heat shock protein.","date":"1996","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/8890154","citation_count":37,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"16940296","id":"PMC_16940296","title":"Tuning of DnaK chaperone action by nonnative protein sensor DnaJ and thermosensor GrpE.","date":"2006","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/16940296","citation_count":37,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"7961459","id":"PMC_7961459","title":"Isolation and characterization of point mutations in the Escherichia coli grpE heat shock gene.","date":"1994","source":"Journal of bacteriology","url":"https://pubmed.ncbi.nlm.nih.gov/7961459","citation_count":35,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"7517454","id":"PMC_7517454","title":"Identification of a grpE heat-shock gene homolog in the archaeon Methanosarcina mazei.","date":"1994","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/7517454","citation_count":35,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"8244960","id":"PMC_8244960","title":"The interplay of the GrpE heat shock protein and Mg2+ in RepA monomerization by DnaJ and DnaK.","date":"1993","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/8244960","citation_count":34,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"368561","id":"PMC_368561","title":"A transducing lambda phage carrying grpE, a bacterial gene necessary for lambda DNA replication, and two ribosomal protein genes, rpsP (S16) and rplS (L19).","date":"1978","source":"Molecular & general genetics : MGG","url":"https://pubmed.ncbi.nlm.nih.gov/368561","citation_count":34,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"29637049","id":"PMC_29637049","title":"Mycobacterium tuberculosis GrpE, A Heat-Shock Stress Responsive Chaperone, Promotes Th1-Biased T Cell Immune Response via TLR4-Mediated Activation of Dendritic Cells.","date":"2018","source":"Frontiers in cellular and infection microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/29637049","citation_count":32,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"8914984","id":"PMC_8914984","title":"Isolation and characterisation of a cDNA encoding rat mitochondrial GrpE, a stress-inducible nucleotide-exchange factor of ubiquitous appearance in mammalian organs.","date":"1996","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/8914984","citation_count":30,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"12840016","id":"PMC_12840016","title":"Free human mitochondrial GrpE is a symmetric dimer in solution.","date":"2003","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12840016","citation_count":27,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"11034484","id":"PMC_11034484","title":"Phylogenetic analysis of gram-positive bacteria based on grpE, encoded by the dnaK operon.","date":"2000","source":"International journal of systematic and evolutionary microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/11034484","citation_count":25,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"9037170","id":"PMC_9037170","title":"Chloroplastic isoforms of DnaJ and GrpE in pea.","date":"1997","source":"Plant molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/9037170","citation_count":25,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"11401497","id":"PMC_11401497","title":"A GrpE mutant containing the NH(2)-terminal \"tail\" region is able to displace bound polypeptide substrate from DnaK.","date":"2001","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/11401497","citation_count":25,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"25739641","id":"PMC_25739641","title":"Modulation of the chaperone DnaK allosterism by the nucleotide exchange factor GrpE.","date":"2015","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/25739641","citation_count":24,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"12054669","id":"PMC_12054669","title":"Hsc62, Hsc56, and GrpE, the third Hsp70 chaperone system of Escherichia coli.","date":"2002","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/12054669","citation_count":24,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"22566698","id":"PMC_22566698","title":"Group A streptococcus adheres to pharyngeal epithelial cells with salivary proline-rich proteins via GrpE chaperone protein.","date":"2012","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/22566698","citation_count":24,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"9276481","id":"PMC_9276481","title":"K+ is an indispensable cofactor for GrpE stimulation of ATPase activity of DnaK x DnaJ complex from Thermus thermophilus.","date":"1997","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/9276481","citation_count":23,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"14627281","id":"PMC_14627281","title":"Induced expression of the heat shock protein genes uspA and grpE during starvation at low temperatures and their influence on thermal resistance of Escherichia coli O157:H7.","date":"2003","source":"Journal of food protection","url":"https://pubmed.ncbi.nlm.nih.gov/14627281","citation_count":23,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"32581108","id":"PMC_32581108","title":"Mitochondrial Import of Dengue Virus NS3 Protease and Cleavage of GrpEL1, a Cochaperone of Mitochondrial Hsp70.","date":"2020","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/32581108","citation_count":22,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"15718032","id":"PMC_15718032","title":"Effects of environmental stresses on the activities of the uspA, grpE and rpoS promoters of Escherichia coli O157:H7.","date":"2005","source":"International journal of food microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/15718032","citation_count":22,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"35093469","id":"PMC_35093469","title":"GrpEL1 regulates mitochondrial unfolded protein response after experimental subarachnoid hemorrhage in vivo and in vitro.","date":"2022","source":"Brain research bulletin","url":"https://pubmed.ncbi.nlm.nih.gov/35093469","citation_count":21,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"20036249","id":"PMC_20036249","title":"Crystal structure of a thermophilic GrpE protein: insight into thermosensing function for the DnaK chaperone system.","date":"2009","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/20036249","citation_count":21,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"8514753","id":"PMC_8514753","title":"Activation of mutant forms of DnaA protein of Escherichia coli by DnaK and GrpE proteins occurs prior to DNA replication.","date":"1993","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/8514753","citation_count":21,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"17976642","id":"PMC_17976642","title":"GrpE N-terminal domain contributes to the interaction with Dnak and modulates the dynamics of the chaperone substrate binding domain.","date":"2007","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/17976642","citation_count":20,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"15485812","id":"PMC_15485812","title":"The DnaK-DnaJ-GrpE chaperone system activates inert wild type pi initiator protein of R6K into a form active in replication initiation.","date":"2004","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/15485812","citation_count":19,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"38253530","id":"PMC_38253530","title":"Structure of the M. tuberculosis DnaK-GrpE complex reveals how key DnaK roles are controlled.","date":"2024","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/38253530","citation_count":19,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"20129077","id":"PMC_20129077","title":"Cloning and characterization of grpE in Acetobacter pasteurianus NBRC 3283.","date":"2009","source":"Journal of bioscience and bioengineering","url":"https://pubmed.ncbi.nlm.nih.gov/20129077","citation_count":18,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"16198374","id":"PMC_16198374","title":"The heat-sensitive Escherichia coli grpE280 phenotype: impaired interaction of GrpE(G122D) with DnaK.","date":"2005","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/16198374","citation_count":18,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"11731148","id":"PMC_11731148","title":"The effect of co-overproduction of DnaK/DnaJ/GrpE and ClpB proteins on the removal of heat-aggregated proteins from Escherichia coli DeltaclpB mutant cells--new insight into the role of Hsp70 in a functional cooperation with Hsp100.","date":"2001","source":"FEMS microbiology letters","url":"https://pubmed.ncbi.nlm.nih.gov/11731148","citation_count":18,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"8390456","id":"PMC_8390456","title":"Activation of DnaA5 protein by GrpE and DnaK heat shock proteins in initiation of DNA replication in Escherichia coli.","date":"1993","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/8390456","citation_count":18,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"11311562","id":"PMC_11311562","title":"Identification and characterization of a human mitochondrial homologue of the bacterial co-chaperone GrpE.","date":"2001","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/11311562","citation_count":17,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"7836285","id":"PMC_7836285","title":"Archaeal grpE: transcription in two different morphologic stages of Methanosarcina mazei and comparison with dnaK and dnaJ.","date":"1995","source":"Journal of bacteriology","url":"https://pubmed.ncbi.nlm.nih.gov/7836285","citation_count":17,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"10777521","id":"PMC_10777521","title":"Heat-inactivated proteins managed by DnaKJ-GrpE-ClpB chaperones are released as a chaperonin-recognizable non-native form.","date":"2000","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10777521","citation_count":17,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"17544398","id":"PMC_17544398","title":"A gram-negative characteristic segment in Escherichia coli DnaK is essential for the ATP-dependent cooperative function with the co-chaperones DnaJ and GrpE.","date":"2007","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/17544398","citation_count":17,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"30258084","id":"PMC_30258084","title":"Comparison of immunogenicity and vaccine efficacy between heat-shock proteins, HSP70 and GrpE, in the DnaK operon of Mycobacterium tuberculosis.","date":"2018","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/30258084","citation_count":16,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"11479711","id":"PMC_11479711","title":"Characterization of stress-responsive genes, hrcA-grpE-dnaK-dnaJ, from phytopathogenic Xanthomonas campestris.","date":"2001","source":"Archives of microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/11479711","citation_count":16,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"32849509","id":"PMC_32849509","title":"GrpE Immunization Protects Against Ureaplasma urealyticum Infection in BALB/C Mice.","date":"2020","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/32849509","citation_count":16,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"16579957","id":"PMC_16579957","title":"Low resolution structure and stability studies of human GrpE#2, a mitochondrial nucleotide exchange factor.","date":"2006","source":"Archives of biochemistry and biophysics","url":"https://pubmed.ncbi.nlm.nih.gov/16579957","citation_count":15,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"1644751","id":"PMC_1644751","title":"The essential Escherichia coli msgB gene, a multicopy suppressor of a temperature-sensitive allele of the heat shock gene grpE, is identical to dapE.","date":"1992","source":"Journal of bacteriology","url":"https://pubmed.ncbi.nlm.nih.gov/1644751","citation_count":15,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"32353859","id":"PMC_32353859","title":"A SARS-CoV-2 protein interaction map reveals targets for drug repurposing.","date":"2020","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/32353859","citation_count":3411,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"22658674","id":"PMC_22658674","title":"Insights into RNA biology from an atlas of mammalian mRNA-binding proteins.","date":"2012","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/22658674","citation_count":1718,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"12477932","id":"PMC_12477932","title":"Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences.","date":"2002","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/12477932","citation_count":1479,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"26186194","id":"PMC_26186194","title":"The BioPlex Network: A Systematic Exploration of the Human Interactome.","date":"2015","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/26186194","citation_count":1118,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"28514442","id":"PMC_28514442","title":"Architecture of the human interactome defines protein communities and disease networks.","date":"2017","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/28514442","citation_count":1085,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"26496610","id":"PMC_26496610","title":"A human interactome in three quantitative dimensions organized by stoichiometries and abundances.","date":"2015","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/26496610","citation_count":1015,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"32296183","id":"PMC_32296183","title":"A reference map of the human binary protein interactome.","date":"2020","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/32296183","citation_count":849,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"29507755","id":"PMC_29507755","title":"VIRMA mediates preferential m6A mRNA methylation in 3'UTR and near stop codon and associates with alternative polyadenylation.","date":"2018","source":"Cell discovery","url":"https://pubmed.ncbi.nlm.nih.gov/29507755","citation_count":829,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"33961781","id":"PMC_33961781","title":"Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.","date":"2021","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/33961781","citation_count":705,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"21873635","id":"PMC_21873635","title":"Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium.","date":"2011","source":"Briefings in bioinformatics","url":"https://pubmed.ncbi.nlm.nih.gov/21873635","citation_count":656,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"33060197","id":"PMC_33060197","title":"Comparative host-coronavirus protein interaction networks reveal pan-viral disease mechanisms.","date":"2020","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/33060197","citation_count":564,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"15489334","id":"PMC_15489334","title":"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).","date":"2004","source":"Genome research","url":"https://pubmed.ncbi.nlm.nih.gov/15489334","citation_count":438,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"26638075","id":"PMC_26638075","title":"A Dynamic Protein Interaction Landscape of the Human Centrosome-Cilium Interface.","date":"2015","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/26638075","citation_count":433,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"26344197","id":"PMC_26344197","title":"Panorama of ancient metazoan macromolecular complexes.","date":"2015","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/26344197","citation_count":407,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"21642987","id":"PMC_21642987","title":"IFIT1 is an antiviral protein that recognizes 5'-triphosphate RNA.","date":"2011","source":"Nature immunology","url":"https://pubmed.ncbi.nlm.nih.gov/21642987","citation_count":405,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"34079125","id":"PMC_34079125","title":"A proximity-dependent biotinylation map of a human cell.","date":"2021","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/34079125","citation_count":339,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"31056398","id":"PMC_31056398","title":"Mitochondrial ClpP-Mediated Proteolysis Induces Selective Cancer Cell Lethality.","date":"2019","source":"Cancer cell","url":"https://pubmed.ncbi.nlm.nih.gov/31056398","citation_count":298,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"22863883","id":"PMC_22863883","title":"A high-throughput approach for measuring temporal changes in the interactome.","date":"2012","source":"Nature methods","url":"https://pubmed.ncbi.nlm.nih.gov/22863883","citation_count":273,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"34800366","id":"PMC_34800366","title":"Quantitative high-confidence human mitochondrial proteome and its dynamics in cellular context.","date":"2021","source":"Cell metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/34800366","citation_count":239,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"26618866","id":"PMC_26618866","title":"∆F508 CFTR interactome remodelling promotes rescue of cystic fibrosis.","date":"2015","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/26618866","citation_count":209,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"29568061","id":"PMC_29568061","title":"An AP-MS- and BioID-compatible MAC-tag enables comprehensive mapping of protein interactions and subcellular localizations.","date":"2018","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/29568061","citation_count":201,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"20186120","id":"PMC_20186120","title":"A functional peptidyl-tRNA hydrolase, ICT1, has been recruited into the human mitochondrial ribosome.","date":"2010","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/20186120","citation_count":153,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"32877691","id":"PMC_32877691","title":"A High-Density Human Mitochondrial Proximity Interaction Network.","date":"2020","source":"Cell metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/32877691","citation_count":148,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"31871319","id":"PMC_31871319","title":"Mapping the proximity interaction network of the Rho-family GTPases reveals signalling pathways and regulatory mechanisms.","date":"2019","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/31871319","citation_count":137,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"29117863","id":"PMC_29117863","title":"RNA-binding activity of TRIM25 is mediated by its PRY/SPRY domain and is required for ubiquitination.","date":"2017","source":"BMC biology","url":"https://pubmed.ncbi.nlm.nih.gov/29117863","citation_count":135,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"35140242","id":"PMC_35140242","title":"Human transcription factor protein interaction networks.","date":"2022","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/35140242","citation_count":123,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"18029348","id":"PMC_18029348","title":"Toward a confocal subcellular atlas of the human proteome.","date":"2007","source":"Molecular & cellular proteomics : MCP","url":"https://pubmed.ncbi.nlm.nih.gov/18029348","citation_count":114,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"26725010","id":"PMC_26725010","title":"KAP1 Recruitment of the 7SK snRNP Complex to Promoters Enables Transcription Elongation by RNA Polymerase II.","date":"2015","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/26725010","citation_count":113,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"34349018","id":"PMC_34349018","title":"Protein interaction landscapes revealed by advanced in vivo cross-linking-mass spectrometry.","date":"2021","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/34349018","citation_count":113,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"34599178","id":"PMC_34599178","title":"Ring finger protein 213 assembles into a sensor for ISGylated proteins with antimicrobial activity.","date":"2021","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/34599178","citation_count":107,"is_preprint":false,"source_track":"gene2pubmed"}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":45467,"output_tokens":1866,"usd":0.082196},"stage2":{"model":"claude-opus-4-6","input_tokens":5120,"output_tokens":4516,"usd":0.20775},"total_usd":0.581949,"stage1_batch_id":"msgbatch_01DzrsgVgYngY1hvM3DU1yF2","stage2_batch_id":"msgbatch_01KA9b7iRzKFdhoBUT7vCvSe","note":"batch pricing = 50% of standard","round2_stage1":{"model":"claude-sonnet-4-6","input_tokens":57049,"output_tokens":6938,"usd":0.137608},"round2_rules_fired":"R3","round2_stage2":{"model":"claude-opus-4-6","input_tokens":7546,"output_tokens":2608,"usd":0.154395}},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2017,\n      \"finding\": \"Human GrpEL1 (and GrpEL2) associate with mitochondrial Hsp70 (mtHsp70) as a hetero-oligomeric subcomplex in human cells, functioning as nucleotide exchange factors (NEFs) that regulate mtHsp70 chaperone activity, mitochondrial preprotein import, and Fe-S cluster biogenesis; GrpEL2 showed preferential stress-resistance function while GrpEL1 was identified as a stress modulator.\",\n      \"method\": \"Co-immunoprecipitation, protein import assays, Fe-S cluster biogenesis assays, knockdown/overexpression in human cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, multiple orthogonal functional assays (import, Fe-S biogenesis, chaperone activity) in human cells with defined phenotypic readouts\",\n      \"pmids\": [\"28848044\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Dengue virus NS3 protease imports into the mitochondrial matrix and cleaves human GrpEL1 at sites KR81A and QR92S, reducing GrpEL1 levels in virus-infected cells and clinical samples; GrpEL1 is a substrate of dengue NS3 protease in vitro and ex vivo.\",\n      \"method\": \"In vitro cleavage assay with purified components, transient transfection, protein import assays, Western blot of clinical samples\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro reconstitution with purified components plus ex vivo validation in infected cells and clinical samples; cleavage sites mapped\",\n      \"pmids\": [\"32581108\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"GrpEL1 forms a complex with mtHsp70 in neurons; this GrpEL1-mtHsp70 complex is reduced after oxyhemoglobin treatment (subarachnoid hemorrhage model), leading to increased protein aggresomes. Overexpression of GrpEL1 restored the complex, decreased aggresomes, increased mitochondrial membrane potential and ATP content, and decreased cleaved-Caspase 9, indicating GrpEL1 promotes mitochondrial protein quality control via mtHsp70.\",\n      \"method\": \"Co-immunoprecipitation, aggresome staining, JC-1 staining, Western blot, overexpression in primary neurons\",\n      \"journal\": \"Brain research bulletin\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — Co-IP showing complex formation, multiple functional readouts in primary neurons, single lab\",\n      \"pmids\": [\"35093469\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Mammalian mitochondrial GrpE#1 (mt-GrpE#1) and mt-GrpE#2 (the human GRPEL1 and GRPEL2 orthologs) bind specifically to E. coli DnaK and are dissociated by 5 mM ATP; both interact with and stimulate the ATPase activity of mammalian mitochondrial Hsp70 (mt-Hsp70), establishing them as functional NEFs for mt-Hsp70.\",\n      \"method\": \"DnaK affinity binding, ATP-dependent dissociation assay, ATPase stimulation assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct binding and ATPase stimulation assays with purified components; first biochemical characterization of mammalian mitochondrial GrpE isoforms\",\n      \"pmids\": [\"9694873\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Human mitochondrial GrpE (HMGE/GrpEL1 ortholog) co-purifies with E. coli DnaK and is released by Mg-ATP; subcellular fractionation and immunocytochemistry show it is a mitochondrial protein; it also interacts with cytosolic Hsc70 and inhibits HSJ1b-enhanced Hsc70 ATPase activity, and directly interacts with the DnaJ-protein HSJ1b.\",\n      \"method\": \"GST pulldown, ATP-dependent release assay, subcellular fractionation, immunocytochemistry, ATPase assay\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — direct binding assays and subcellular localization with functional consequence; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"11311562\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Free human mitochondrial GrpE (GrpEL1 ortholog) is a symmetric dimer in solution with an elongated cruciform shape as determined by analytical ultracentrifugation and small-angle X-ray scattering, distinct from the asymmetric conformation it adopts when bound to DnaK.\",\n      \"method\": \"Analytical ultracentrifugation, small-angle X-ray scattering, circular dichroism\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — structural characterization by SAXS and AUC; single lab but orthogonal biophysical methods\",\n      \"pmids\": [\"12840016\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Human mitochondrial GrpE isoform 2 (GrpEL2) forms a dimer with a cruciform elongated shape similar to GrpEL1 and E. coli GrpE by SAXS, but differs from GrpEL1 in chemical and thermal denaturation profiles, suggesting functional divergence between the two human mitochondrial GrpE isoforms.\",\n      \"method\": \"Small-angle X-ray scattering, circular dichroism, thermal/chemical denaturation\",\n      \"journal\": \"Archives of biochemistry and biophysics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — structural characterization distinguishing the two human isoforms; single lab with multiple biophysical methods\",\n      \"pmids\": [\"16979957\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"GRPEL1 is a mitochondrial nucleotide exchange factor (NEF) that forms a hetero-oligomeric subcomplex with GRPEL2 and mitochondrial Hsp70 (mtHsp70) in human cells, promoting ADP-to-ATP exchange at mtHsp70's nucleotide-binding domain to drive chaperone cycles required for mitochondrial preprotein import, Fe-S cluster biogenesis, and mitochondrial protein quality control; it is subject to cleavage by dengue virus NS3 protease at defined sites, and its interaction with mtHsp70 maintains mitochondrial homeostasis under stress conditions.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nI'll classify each paper and extract discoveries only from KEEP papers.\n\n**Classification:**\n\n**KEEP (canonical GRPEL1/mammalian mitochondrial GrpE):**\n- PMID:28848044 — directly about GrpEL1 and GrpEL2 in human cells\n- PMID:32581108 — directly about GrpEL1 cleavage by dengue NS3\n- PMID:35093469 — directly about GrpEL1 role in UPRmt after SAH\n- PMID:9694873 — mammalian mt-GrpE#1 and #2 (GRPEL1/GRPEL2 orthologs)\n- PMID:12840016 — human mitochondrial GrpE (GRPEL1) structural studies\n- PMID:16979957 — human GrpE#2 biophysical studies (relevant context)\n- PMID:11311562 — human HMGE (GRPEL1 ortholog) characterization\n- PMID:8022808 — yeast Mge1p (ortholog, foundational)\n- PMID:8168496 — yeast GrpE (ortholog, foundational)\n- PMID:7628446 — yeast Mge1p function (ortholog)\n- PMID:7935381 — mitochondrial GrpE/MGE in Neurospora/yeast (ortholog)\n- PMID:8524277 — yeast Mge1p (ortholog)\n- PMID:9237899 — yeast Mge1p ATPase cycle (ortholog)\n- PMID:8166717 — yeast Yge1p (ortholog)\n- PMID:8112465 — yeast YGE1 (ortholog)\n- PMID:8914984 — rat mt-GrpE (ortholog)\n- PMID:16959957 — human GrpE#2 (GRPEL2, different paralog — still relevant context)\n\n**KEEP from curated list:**\n- PMID:32353859 — SARS-CoV-2 interactome (GRPEL1 identified as interactor)\n- PMID:33060197 — comparative coronavirus interactions\n- PMID:34800366 — mitochondrial proteome (GRPEL1 quantified)\n- PMID:32877691 — mitochondrial BioID proximity map\n\n**EXCLUDE (E. coli/bacterial GrpE not ortholog context, plant GrpE, Mtb GrpE immune studies, unrelated papers):**\nMost of the 100 retrieved papers are about bacterial E. coli GrpE (DnaK system) — these describe the prokaryotic protein. However, the foundational mechanistic work on the bacterial system is the basis for understanding the eukaryotic mitochondrial GRPEL1. Per instructions, orthologs in model organisms should be KEPT if function/domain architecture are consistent. The yeast/mammalian papers are clear orthologs. The E. coli papers describe the founding mechanism. I'll include key E. coli mechanistic papers as foundational orthologs since the mammalian GRPEL1 functions by the same mechanism.\n\n**Re-evaluating E. coli papers:** The corpus is predominantly E. coli GrpE papers. The mammalian GRPEL1 is the direct functional ortholog. I'll include key mechanistic E. coli papers plus all mammalian/yeast papers.\n\n**EXCLUDE definitively:**\n- PMID:503859 — HMG proteins, completely unrelated\n- PMID:11752390 — Chlamydomonas chloroplast CGE1 (plant chloroplast, symbol collision context)\n- PMID:22128139 — Arabidopsis Mge (plant, symbol collision)\n- PMID:9037170 — pea chloroplast (plant)\n- PMID:29637049 — Mtb GrpE immune/vaccine study\n- PMID:30258084 — Mtb GrpE vaccine\n- PMID:32849509 — Ureaplasma GrpE vaccine\n- PMID:14627281 — E. coli O157 expression only\n- PMID:15718032 — E. coli O157 promoter expression\n- PMID:16109938 — Pseudomonas putisolvin regulation\n- PMID:22566698 — GAS GrpE adhesion (Streptococcus)\n- PMID:1400176 — flagellum synthesis (E. coli phenotype, no direct mechanism for GRPEL1)\n- PMID:8606155 — Caulobacter hrcA/grpE regulation\n- PMID:1577695 — Clostridium dnaK operon\n- PMID:9282745 — Streptococcus mutans heat shock\n- PMID:11034484 — phylogenetic analysis\n- PMID:8459764 — Borrelia burgdorferi cloning\n- PMID:20129077 — Acetobacter pasteurianus\n- PMID:11479711 — Xanthomonas campestris\n- PMID:7517454 — archaeal grpE\n- PMID:7836285 — archaeal grpE transcription\n- PMID:368561 — transducing lambda phage mapping\n- PMID:2424889 — grpE gene identification (E. coli)\n- PMID:2651417 — grpE deletion (E. coli genetics)\n- PMID:3045760 — grpE sequence/transcription (E. coli)\n- PMID:2527744 — lambda DNA replication (E. coli)\n- PMID:1438220 — P1 plasmid replication\n- PMID:8501058 — P1 plasmid RepA binding\n- PMID:2681150 — P1 plasmid replication\n- PMID:2183004 — mini-F plasmid replication\n- PMID:1534276 — sigma32 physical interaction\n- PMID:8599944 — sigma32 regulation cycle\n- PMID:1361234 — lambda P protein sequestering\n- PMID:8444859 — lambda DNA replication\n- PMID:8514753 — DnaA5 activation\n- PMID:8390456 — DnaA5 activation\n- PMID:1644751 — msgB/dapE suppressor\n- PMID:7961459 — grpE point mutations\n- PMID:9572938 — chaperone coexpression plasmids\n- PMID:10497158 — ClpB cooperation\n- PMID:10377389 — Thermus thermophilus DnaKJ\n- PMID:9852006 — Hsc66-Hsc20 system\n- PMID:14984054 — GrpE review\n- PMID:25487014 — NEF review\n- PMID:9321400 — BAG-1/Hsc70 (BAG1 not GRPEL1)\n- PMID:15632130 — trigger factor\n- PMID:18599817 — GrpE overexpression cell division\n- PMID:12054669 — Hsc62/Hsc56/GrpE third system\n- PMID:15102842 — GrpE influence on DnaK substrates\n- PMID:14731284 — Hsp31 cooperation\n- PMID:11731148 — ClpB cooperation\n- PMID:15485812 — R6K plasmid\n- PMID:16940296 — DnaK tuning\n- PMID:16198374 — grpE280 phenotype\n- PMID:17976642 — GrpE N-terminal domain DnaK\n- PMID:25739641 — DnaK allosterism GrpE\n- PMID:20036249 — thermophilic GrpE structure\n- PMID:11724541 — GrpE thermosensor\n- PMID:11401497 — GrpE tail mutant\n- PMID:17544398 — gram-negative DnaK segment\n- PMID:9276481 — K+ cofactor Thermus\n- PMID:9506960 — substoichiometric co-chaperones\n- PMID:9657681 — temperature-controlled activity\n- PMID:9131990 — associative displacement mechanism\n- PMID:9223639 — power stroke DnaK/DnaJ/GrpE\n- PMID:7876226 — modulation of ATPase\n- PMID:7836448 — DnaK-GrpE quaternary structures\n- PMID:9103205 — crystal structure GrpE-DnaK (E. coli)\n- PMID:22544739 — G. kaustophilus DnaK-GrpE crystal structure\n- PMID:38253530 — Mtb DnaK-GrpE cryo-EM\n- PMID:8244960 — RepA monomerization\n- PMID:7902351 — RNA polymerase reactivation\n- PMID:9506960 — substoichiometric GrpE\n- PMID:8898387 — protein folding cytoplasm\n- PMID:8655561 — protein secretion\n- PMID:1826368 — ATPase stimulation (foundational)\n- PMID:7900997 — chaperone repair (foundational)\n- PMID:7937953 — ATP hydrolysis cycle (foundational)\n- PMID:8890154 — GrpE structure-function\n- PMID:7656024 — conserved loop DnaK-GrpE binding\n- PMID:25451597 — ClpB-DnaK-GrpE interplay\n- PMID:11376662 — DnaK linker mutations\n- PMID:9506960 — substoichiometric\n- PMID:7836448 — quaternary structures\n\nNow, focusing on papers that are specifically about the mammalian GRPEL1 protein:\n\n**Definitive KEEP for GRPEL1:**\n1. PMID:28848044 — Human GrpEL1 and GrpEL2\n2. PMID:32581108 — Dengue NS3 cleavage of GrpEL1\n3. PMID:35093469 — GrpEL1 in UPRmt after SAH\n4. PMID:9694873 — Mammalian mt-GrpE#1/#2 (GRPEL1/GRPEL2)\n5. PMID:12840016 — Human mitochondrial GrpE (GRPEL1) structure\n6. PMID:11311562 — Human HMGE (GRPEL1)\n7. PMID:8914984 — Rat mt-GrpE (GRPEL1 ortholog)\n8. PMID:16979957 — Human GrpE#2 biophysical (GRPEL2 — paralog context)\n9. PMID:8022808 — Yeast Mge1p (foundational ortholog)\n10. PMID:8168496 — Yeast GrpE (foundational ortholog)\n11. PMID:7628446 — Yeast Mge1p mechanism\n12. PMID:7935381 — Mitochondrial GrpE/MGE (Neurospora/yeast)\n13. PMID:8524277 — Yeast Mge1p import/folding\n14. PMID:9237899 — Yeast Mge1p ATPase cycle\n15. PMID:8166717 — Yeast Yge1p\n16. PMID:8112465 — Yeast YGE1\n\nFrom curated list (KEEP mechanistic):\n- PMID:32353859 — SARS-CoV-2 interactome (GRPEL1 as interactor — pulldown MS)\n- PMID:33060197 — coronavirus interactions\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1994,\n      \"finding\": \"Mge1p (yeast mitochondrial GrpE/GRPEL1 ortholog) was identified as the first eukaryotic GrpE-related protein, shown to be an essential nuclear-encoded soluble protein of the mitochondrial matrix that cooperates with mitochondrial Hsp70 (mt-Hsp70) in protein translocation into mitochondria; cells with reduced Mge1p accumulate mitochondrial precursor proteins.\",\n      \"method\": \"Yeast genetics, subcellular fractionation, precursor import assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — foundational ortholog study with genetic depletion, import assays, and functional demonstration; replicated by multiple independent labs\",\n      \"pmids\": [\"8022808\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"Yeast GrpEp (GRPEL1 ortholog) is made as a precursor that is cleaved upon import into mitochondria, physically interacts with mitochondrial Hsp70 (mt-Hsp70) via ATP-sensitive binding, is essential for viability, and functions analogously to bacterial GrpE with DnaK.\",\n      \"method\": \"Affinity purification with His-tagged mt-Hsp70, ATP dissociation assay, gene cloning, microsequencing, mitochondrial import assay\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — biochemical reconstitution, affinity purification, ATP-dependent dissociation, microsequencing validation; independent replication\",\n      \"pmids\": [\"8168496\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"Yeast Yge1p (GRPEL1 ortholog) localizes to the mitochondrial matrix as a soluble protein, physically interacts with mitochondrial Hsp70 (Ssc1p) by co-immunoprecipitation, is essential for cell viability, and is required for protein import into mitochondria (depletion causes precursor accumulation of F1-ATPase β subunit).\",\n      \"method\": \"Co-immunoprecipitation, subcellular fractionation, in vivo precursor accumulation assay\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — co-IP plus functional import assay, ortholog confirmed in independent lab\",\n      \"pmids\": [\"8112465\", \"8166717\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"Mitochondrial GrpE (MGE, GRPEL1 ortholog) in Neurospora crassa and S. cerevisiae is quantitatively bound to matrix mt-Hsp70, released by Mg-ATP (but not non-hydrolyzable analogs or high salt), and co-precipitates with preproteins in transit across mitochondrial membranes, demonstrating that mt-Hsp70 and MGE cooperate in membrane translocation.\",\n      \"method\": \"Immunoprecipitation with anti-MGE and anti-mt-Hsp70 antibodies, ATP-dependent dissociation assay, import intermediate trapping\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal immunoprecipitation, ATP-dependent release, import intermediate co-precipitation; cross-species validation\",\n      \"pmids\": [\"7935381\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"Yeast Mge1p (GRPEL1 ortholog) conditional mutants impair mt-Hsp70 binding to incoming precursor proteins, reduce nucleotide-dependent dissociation of mt-Hsp70 from MIM44, and cause increased protein aggregation and incomplete folding of newly imported proteins; Mge1p promotes the progress of the Hsp70 reaction cycle for protein import and folding.\",\n      \"method\": \"Temperature-sensitive mge1 mutants, mitochondrial import kinetics assay, mt-Hsp70–MIM44 interaction assay, protein aggregation assay\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — conditional mutant with multiple functional readouts (import kinetics, Hsp70-MIM44 interaction, folding, aggregation); mechanistically detailed\",\n      \"pmids\": [\"7628446\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"Yeast Mge1p (GRPEL1 ortholog) mutant mitochondria show defective mt-Hsp70 binding to translocating precursors and impaired maturation (retarded second proteolytic processing); wild-type Mge1p promotes mt-Hsp70 cycling by modulating nucleotide-dependent substrate binding.\",\n      \"method\": \"Conditional mge1 mutants, preprotein import assay, proteolytic processing assay, mt-Hsp70–preprotein interaction measurements\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic mutant combined with biochemical import and processing assays; independent confirmation of Mge1p mechanism\",\n      \"pmids\": [\"8524277\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Yeast Mge1p (GRPEL1 ortholog) stimulates ATP hydrolysis by mt-Hsp70 approximately 2-fold and promotes the ATPase cycle by increasing the rate of ADP release rather than directly affecting phosphate release; inorganic phosphate inhibits ATP hydrolysis by preventing ADP release, and Mge1p relieves this phosphate inhibition.\",\n      \"method\": \"In vitro ATPase assay with purified recombinant mt-Hsp70 and Mge1p, phosphate inhibition experiments\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro biochemical reconstitution with purified components; mechanistic dissection of nucleotide exchange\",\n      \"pmids\": [\"9237899\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"Rat mitochondrial GrpE (mt-GrpE, GRPEL1 ortholog) is a 21 kDa nuclear-encoded protein present exclusively in the mitochondrial fraction; its transcript is expressed in most organs; unlike other mitochondrial chaperones, mt-GrpE levels are only marginally increased by heat shock or proline analog stress, suggesting constitutive expression.\",\n      \"method\": \"cDNA cloning, Western blotting of subcellular fractions, Northern blotting across tissues, stress induction experiments\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — biochemical fractionation with localization, but primary findings are expression-level; functional characterization limited\",\n      \"pmids\": [\"8914984\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Two mammalian mitochondrial GrpE-like proteins (mt-GrpE#1/GRPEL1 and mt-GrpE#2/GRPEL2) were identified; both bind specifically to E. coli DnaK in an ATP-dissociable manner, interact with mammalian mt-Hsp70, and stimulate its ATPase activity; they share ~47% amino acid identity and differ in 3'-UTR destabilization elements, suggesting different post-transcriptional regulation.\",\n      \"method\": \"DnaK affinity binding assay, ATP dissociation, ATPase stimulation assay with purified mammalian mt-Hsp70, cDNA cloning, sequence analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — biochemical binding assays, ATPase stimulation, multi-method characterization of both paralogs in the same study\",\n      \"pmids\": [\"9694873\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Human HMGE (GRPEL1 ortholog) was identified as a mitochondrial protein that co-purifies with E. coli DnaK and is released by Mg-ATP; it also binds cytosolic Hsc70 and the DnaJ-domain protein HSJ1b; HMGE inhibits HSJ1b-enhanced Hsc70 ATPase activity and may interact directly with DnaJ proteins, representing the first reported DnaJ–GrpE direct interaction.\",\n      \"method\": \"GST pulldown with DnaK, ATP dissociation assay, subcellular fractionation, immunocytochemistry, co-immunoprecipitation with Hsc70 and HSJ1b, ATPase inhibition assay\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — multiple biochemical assays but single lab; interaction with cytosolic Hsc70 is unexpected and awaits independent confirmation\",\n      \"pmids\": [\"11311562\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Free human mitochondrial GrpE (GRPEL1) forms a symmetric dimer in solution, with an elongated cruciform shape as determined by analytical ultracentrifugation and small-angle X-ray scattering; the symmetric dimer becomes asymmetric upon DnaK binding, suggesting a conformational change upon complex formation.\",\n      \"method\": \"Circular dichroism, differential scanning calorimetry, analytical ultracentrifugation, small-angle X-ray scattering (SAXS)\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — multiple biophysical methods (SAXS, AUC, CD, DSC) providing convergent structural evidence\",\n      \"pmids\": [\"12840016\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Human GrpEL1 and GrpEL2 both associate with mtHsp70 as a hetero-oligomeric subcomplex in human cells; this hetero-oligomeric complex formation is critical for conferring stability to both NEFs; GrpEL1 and GrpEL2 together regulate mtHsp70-dependent import of preproteins and biogenesis of Fe-S clusters; GrpEL2 has evolved as a stress-resistance protein, while GrpEL1 functions as a stress modulator.\",\n      \"method\": \"Co-immunoprecipitation, RNAi knockdown, mitochondrial preprotein import assay, Fe-S cluster biogenesis assay, stability assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (co-IP, functional import assays, Fe-S biogenesis, stability), direct study of human GrpEL1 and GrpEL2\",\n      \"pmids\": [\"28848044\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Dengue virus NS3 protease is imported into the mitochondrial matrix via an intrinsic mitochondrial transport signal and cleaves GrpEL1 at sites KR81A and QR92S; GrpEL1 levels are reduced in NS3-expressing cells, NS3-helicase-expressing cells, virus-infected cells, and severe dengue clinical samples, identifying GrpEL1 as a substrate of dengue NS3 protease.\",\n      \"method\": \"In silico MTS prediction, transient transfection, mitochondrial import assay, purified component cleavage assay, site mapping, Western blotting in clinical samples\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro cleavage with purified components, site mapping by mutagenesis, validated ex vivo in virus-infected cells and clinical samples\",\n      \"pmids\": [\"32581108\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"After subarachnoid hemorrhage (SAH), the GrpEL1–mtHsp70 complex is reduced in neurons; overexpression of GrpEL1 increases GrpEL1–mtHsp70 complex formation (by co-immunoprecipitation), decreases protein aggresomes, improves mitochondrial membrane potential, increases ATP content, and decreases cleaved Caspase-9, demonstrating that the GrpEL1–mtHsp70 interaction is essential for mitochondrial protein quality control and neuronal survival after SAH.\",\n      \"method\": \"Co-immunoprecipitation, aggresome staining, JC-1 mitochondrial membrane potential assay, ATP measurement, Western blot (cleaved Caspase-9), GrpEL1 overexpression in primary neurons\",\n      \"journal\": \"Brain research bulletin\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — co-IP plus functional readouts (aggresomes, membrane potential, ATP, apoptosis) in cellular model; single lab, disease-specific context\",\n      \"pmids\": [\"35093469\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"GRPEL1 was identified as a physical interactor of SARS-CoV-2 proteins by affinity-purification mass spectrometry in human cells, placing it within the host-virus protein interaction network.\",\n      \"method\": \"Affinity-purification mass spectrometry (AP-MS) of tagged SARS-CoV-2 proteins in HEK293T cells\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single AP-MS dataset; interaction identified but not mechanistically validated for GRPEL1 specifically\",\n      \"pmids\": [\"32353859\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"GRPEL1 is a nuclear-encoded mitochondrial matrix protein that forms a hetero-oligomeric complex with its paralog GRPEL2, functions as a nucleotide exchange factor (NEF) for mitochondrial Hsp70 (mtHsp70) by promoting ADP release and ATP rebinding, and thereby drives mtHsp70-dependent preprotein import, Fe-S cluster biogenesis, and mitochondrial protein quality control; it is cleaved and inactivated by dengue virus NS3 protease at sites KR81A/QR92S, and its reduced interaction with mtHsp70 leads to accumulation of protein aggresomes and mitochondrial dysfunction.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"GRPEL1 is a mitochondrial nucleotide exchange factor (NEF) that functions as a symmetric homodimer and forms a hetero-oligomeric subcomplex with GRPEL2 and mitochondrial Hsp70 (mtHsp70), stimulating ADP-to-ATP exchange to drive mtHsp70 chaperone cycling required for mitochondrial preprotein import, Fe–S cluster biogenesis, and mitochondrial protein quality control [PMID:9694873, PMID:28848044]. The free GRPEL1 dimer adopts an elongated cruciform shape in solution that differs from the asymmetric conformation it assumes when bound to its Hsp70 partner [PMID:12840016]. Interaction of GRPEL1 with mtHsp70 maintains mitochondrial membrane potential and suppresses protein aggregation and caspase-9-dependent apoptosis under stress conditions in neurons [PMID:35093469]. Dengue virus NS3 protease enters the mitochondrial matrix and cleaves GRPEL1 at defined sites (KR81↓A and QR92↓S), reducing GRPEL1 levels during infection and thereby subverting mitochondrial homeostasis [PMID:32581108].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Establishing the basic biochemical identity of mammalian mitochondrial GrpE proteins: GRPEL1 and GRPEL2 were shown to bind Hsp70-family chaperones in an ATP-regulated manner and to stimulate their ATPase activity, defining them as bona fide nucleotide exchange factors for mtHsp70.\",\n      \"evidence\": \"DnaK affinity binding, ATP-dependent dissociation, and ATPase stimulation assays with purified recombinant proteins\",\n      \"pmids\": [\"9694873\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Endogenous stoichiometry and relative contributions of GRPEL1 vs GRPEL2 in human mitochondria were not addressed\",\n        \"No structural information on the GRPEL1–mtHsp70 complex\"\n      ]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Confirming GRPEL1 as a mitochondrial protein and revealing an unexpected interaction with cytosolic Hsc70/HSJ1b, raising the question of whether GRPEL1 has extra-mitochondrial functions.\",\n      \"evidence\": \"Subcellular fractionation, immunocytochemistry, GST pulldown, and ATPase assays in human cells\",\n      \"pmids\": [\"11311562\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Cytosolic Hsc70/HSJ1b interaction not confirmed by reciprocal pulldown or in intact cells\",\n        \"Physiological relevance of the cytosolic interaction remains unclear\"\n      ]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Determining the solution structure of free GRPEL1 as a symmetric elongated cruciform dimer, contrasting with the asymmetric conformation adopted upon DnaK binding and suggesting conformational rearrangement during the chaperone cycle.\",\n      \"evidence\": \"Analytical ultracentrifugation, small-angle X-ray scattering, and circular dichroism of purified recombinant GRPEL1\",\n      \"pmids\": [\"12840016\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No high-resolution atomic structure of free GRPEL1 or the GRPEL1–mtHsp70 complex\",\n        \"Conformational change mechanism upon Hsp70 binding not directly captured\"\n      ]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Demonstrating that GRPEL2 shares the overall cruciform dimer architecture of GRPEL1 but differs in stability and denaturation profiles, providing a structural basis for functional divergence between the two human mitochondrial GrpE isoforms.\",\n      \"evidence\": \"SAXS, circular dichroism, and thermal/chemical denaturation of purified GRPEL2 compared with GRPEL1\",\n      \"pmids\": [\"16979957\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether the two isoforms form obligate heterodimers or function as homodimers in vivo was unresolved\",\n        \"Functional consequences of the stability differences not tested in cells\"\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Resolving the in vivo organization: GRPEL1 and GRPEL2 associate as a hetero-oligomeric subcomplex with mtHsp70 and are jointly required for mitochondrial preprotein import and Fe–S cluster biogenesis, with GRPEL2 preferentially maintaining function under stress while GRPEL1 acts as a stress modulator.\",\n      \"evidence\": \"Reciprocal co-immunoprecipitation, protein import assays, Fe–S cluster biogenesis assays, and knockdown/overexpression in human cells\",\n      \"pmids\": [\"28848044\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis of hetero-oligomer formation and whether GRPEL1/GRPEL2 ratio is regulated\",\n        \"Precise mechanism by which GRPEL1 modulates stress response versus GRPEL2\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identifying GRPEL1 as a direct substrate of dengue virus NS3 protease, which enters the mitochondrial matrix and cleaves GRPEL1 at two defined sites, providing a viral strategy to disrupt mitochondrial chaperone function during infection.\",\n      \"evidence\": \"In vitro cleavage assay with purified NS3 protease and GRPEL1, transient transfection, and Western blot validation in clinical dengue samples\",\n      \"pmids\": [\"32581108\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Downstream consequences of GRPEL1 cleavage on import, Fe–S biogenesis, and innate immune signaling not fully delineated\",\n        \"Whether other flavivirus NS3 proteases target GRPEL1 is unknown\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Demonstrating that the GRPEL1–mtHsp70 complex is critical for neuronal mitochondrial protein quality control: loss of this complex after hemorrhagic insult leads to protein aggregation and apoptosis, while GRPEL1 overexpression restores mitochondrial function.\",\n      \"evidence\": \"Co-immunoprecipitation, aggresome staining, JC-1 mitochondrial membrane potential assay, and Western blot in primary neurons treated with oxyhemoglobin\",\n      \"pmids\": [\"35093469\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single-lab finding in one stress model; generalizability to other neuronal insults not tested\",\n        \"Mechanism by which stress reduces the GRPEL1–mtHsp70 complex not identified\",\n        \"In vivo confirmation in animal models lacking\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"A high-resolution structure of the GRPEL1–GRPEL2–mtHsp70 hetero-oligomeric complex is needed to understand how the two NEF isoforms cooperate in nucleotide exchange and how their ratio is regulated under normal and stress conditions.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No atomic-resolution structure of the native ternary complex\",\n        \"Regulatory mechanisms controlling GRPEL1/GRPEL2 stoichiometry are unknown\",\n        \"Whether GRPEL1 loss alone is sufficient for disease phenotypes in vivo has not been tested\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\n        \"term_id\": \"GO:0098772\",\n        \"supporting_discovery_ids\": [0, 3, 4]\n      }\n    ],\n    \"localization\": [\n      {\n        \"term_id\": \"GO:0005739\",\n        \"supporting_discovery_ids\": [0, 1, 2, 4]\n      }\n    ],\n    \"pathway\": [\n      {\n        \"term_id\": \"GO:0098772\",\n        \"supporting_discovery_ids\": []\n      }\n    ],\n    \"complexes\": [\n      \"GRPEL1–GRPEL2–mtHsp70 hetero-oligomeric complex\"\n    ],\n    \"partners\": [\n      \"HSPA9\",\n      \"GRPEL2\",\n      \"HSPA8\",\n      \"DNAJB2\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\nWait, I need to fix the pathway field. The allowed pathway term_ids are Reactome IDs, not GO IDs. Let me correct this.\n\n```json\n{\n  \"mechanistic_narrative\": \"GRPEL1 is a mitochondrial nucleotide exchange factor (NEF) that functions as a symmetric homodimer and forms a hetero-oligomeric subcomplex with GRPEL2 and mitochondrial Hsp70 (mtHsp70), stimulating ADP-to-ATP exchange to drive mtHsp70 chaperone cycling required for mitochondrial preprotein import, Fe–S cluster biogenesis, and mitochondrial protein quality control [PMID:9694873, PMID:28848044]. The free GRPEL1 dimer adopts an elongated cruciform shape in solution that differs from the asymmetric conformation it assumes when bound to its Hsp70 partner [PMID:12840016]. Interaction of GRPEL1 with mtHsp70 maintains mitochondrial membrane potential and suppresses protein aggregation and caspase-9-dependent apoptosis under stress conditions in neurons [PMID:35093469]. Dengue virus NS3 protease enters the mitochondrial matrix and cleaves GRPEL1 at defined sites (KR81↓A and QR92↓S), reducing GRPEL1 levels during infection and thereby subverting mitochondrial homeostasis [PMID:32581108].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Establishing the basic biochemical identity of mammalian mitochondrial GrpE proteins: GRPEL1 and GRPEL2 were shown to bind Hsp70-family chaperones in an ATP-regulated manner and to stimulate their ATPase activity, defining them as bona fide nucleotide exchange factors for mtHsp70.\",\n      \"evidence\": \"DnaK affinity binding, ATP-dependent dissociation, and ATPase stimulation assays with purified recombinant proteins\",\n      \"pmids\": [\"9694873\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Endogenous stoichiometry and relative contributions of GRPEL1 vs GRPEL2 in human mitochondria were not addressed\",\n        \"No structural information on the GRPEL1–mtHsp70 complex\"\n      ]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Confirming GRPEL1 as a mitochondrial protein and revealing an unexpected interaction with cytosolic Hsc70/HSJ1b, raising the question of whether GRPEL1 has extra-mitochondrial functions.\",\n      \"evidence\": \"Subcellular fractionation, immunocytochemistry, GST pulldown, and ATPase assays in human cells\",\n      \"pmids\": [\"11311562\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Cytosolic Hsc70/HSJ1b interaction not confirmed by reciprocal pulldown or in intact cells\",\n        \"Physiological relevance of the cytosolic interaction remains unclear\"\n      ]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Determining the solution structure of free GRPEL1 as a symmetric elongated cruciform dimer, contrasting with the asymmetric conformation adopted upon DnaK binding and suggesting conformational rearrangement during the chaperone cycle.\",\n      \"evidence\": \"Analytical ultracentrifugation, small-angle X-ray scattering, and circular dichroism of purified recombinant GRPEL1\",\n      \"pmids\": [\"12840016\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No high-resolution atomic structure of free GRPEL1 or the GRPEL1–mtHsp70 complex\",\n        \"Conformational change mechanism upon Hsp70 binding not directly captured\"\n      ]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Demonstrating that GRPEL2 shares the overall cruciform dimer architecture of GRPEL1 but differs in stability and denaturation profiles, providing a structural basis for functional divergence between the two human mitochondrial GrpE isoforms.\",\n      \"evidence\": \"SAXS, circular dichroism, and thermal/chemical denaturation of purified GRPEL2 compared with GRPEL1\",\n      \"pmids\": [\"16979957\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether the two isoforms form obligate heterodimers or function as homodimers in vivo was unresolved\",\n        \"Functional consequences of the stability differences not tested in cells\"\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Resolving the in vivo organization: GRPEL1 and GRPEL2 associate as a hetero-oligomeric subcomplex with mtHsp70 and are jointly required for mitochondrial preprotein import and Fe–S cluster biogenesis, with GRPEL2 preferentially maintaining function under stress while GRPEL1 acts as a stress modulator.\",\n      \"evidence\": \"Reciprocal co-immunoprecipitation, protein import assays, Fe–S cluster biogenesis assays, and knockdown/overexpression in human cells\",\n      \"pmids\": [\"28848044\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis of hetero-oligomer formation and whether GRPEL1/GRPEL2 ratio is regulated\",\n        \"Precise mechanism by which GRPEL1 modulates stress response versus GRPEL2\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identifying GRPEL1 as a direct substrate of dengue virus NS3 protease, which enters the mitochondrial matrix and cleaves GRPEL1 at two defined sites, providing a viral strategy to disrupt mitochondrial chaperone function during infection.\",\n      \"evidence\": \"In vitro cleavage assay with purified NS3 protease and GRPEL1, transient transfection, and Western blot validation in clinical dengue samples\",\n      \"pmids\": [\"32581108\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Downstream consequences of GRPEL1 cleavage on import, Fe–S biogenesis, and innate immune signaling not fully delineated\",\n        \"Whether other flavivirus NS3 proteases target GRPEL1 is unknown\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Demonstrating that the GRPEL1–mtHsp70 complex is critical for neuronal mitochondrial protein quality control: loss of this complex after hemorrhagic insult leads to protein aggregation and apoptosis, while GRPEL1 overexpression restores mitochondrial function.\",\n      \"evidence\": \"Co-immunoprecipitation, aggresome staining, JC-1 mitochondrial membrane potential assay, and Western blot in primary neurons treated with oxyhemoglobin\",\n      \"pmids\": [\"35093469\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single-lab finding in one stress model; generalizability to other neuronal insults not tested\",\n        \"Mechanism by which stress reduces the GRPEL1–mtHsp70 complex not identified\",\n        \"In vivo confirmation in animal models lacking\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"A high-resolution structure of the GRPEL1–GRPEL2–mtHsp70 hetero-oligomeric complex is needed to understand how the two NEF isoforms cooperate in nucleotide exchange and how their ratio is regulated under normal and stress conditions.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No atomic-resolution structure of the native ternary complex\",\n        \"Regulatory mechanisms controlling GRPEL1/GRPEL2 stoichiometry are unknown\",\n        \"Whether GRPEL1 loss alone is sufficient for disease phenotypes in vivo has not been tested\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\n        \"term_id\": \"GO:0098772\",\n        \"supporting_discovery_ids\": [0, 3, 4]\n      }\n    ],\n    \"localization\": [\n      {\n        \"term_id\": \"GO:0005739\",\n        \"supporting_discovery_ids\": [0, 1, 2, 4]\n      }\n    ],\n    \"pathway\": [\n      {\n        \"term_id\": \"R-HSA-9609507\",\n        \"supporting_discovery_ids\": [0]\n      },\n      {\n        \"term_id\": \"R-HSA-392499\",\n        \"supporting_discovery_ids\": [0, 2]\n      }\n    ],\n    \"complexes\": [\n      \"GRPEL1–GRPEL2–mtHsp70 hetero-oligomeric complex\"\n    ],\n    \"partners\": [\n      \"HSPA9\",\n      \"GRPEL2\",\n      \"HSPA8\",\n      \"DNAJB2\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"GRPEL1 is a nuclear-encoded mitochondrial matrix nucleotide exchange factor (NEF) that drives the ATPase cycle of mitochondrial Hsp70 (mtHsp70) by accelerating ADP release, thereby enabling mtHsp70-dependent preprotein import, iron-sulfur cluster biogenesis, and mitochondrial protein quality control [PMID:8022808, PMID:9237899, PMID:28848044]. GRPEL1 forms a homodimer in its free state and assembles into a hetero-oligomeric complex with its paralog GRPEL2, a partnership that confers mutual stability and is required for full NEF activity toward mtHsp70 [PMID:12840016, PMID:28848044]. Loss of GrpEL1–mtHsp70 interaction leads to accumulation of protein aggresomes, impaired mitochondrial membrane potential, and apoptotic signaling [PMID:35093469]. Dengue virus NS3 protease enters the mitochondrial matrix and cleaves GRPEL1 at KR81↓A and QR92↓S, reducing its steady-state levels during infection and in severe dengue patient samples [PMID:32581108].\",\n  \"teleology\": [\n    {\n      \"year\": 1994,\n      \"claim\": \"Identification of a mitochondrial GrpE homolog answered whether eukaryotic mitochondria possess a dedicated Hsp70 nucleotide exchange factor; yeast Mge1p was shown to be an essential, nuclear-encoded, matrix-localized protein required for preprotein import.\",\n      \"evidence\": \"Yeast genetics, subcellular fractionation, import assays, co-immunoprecipitation, and ATP-dependent dissociation from mt-Hsp70 across S. cerevisiae and N. crassa\",\n      \"pmids\": [\"8022808\", \"8168496\", \"8112465\", \"7935381\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Mammalian ortholog not yet characterized\",\n        \"Mechanism of nucleotide exchange not dissected at the kinetic level\",\n        \"Structural basis of the GrpE–Hsp70 interaction unknown\"\n      ]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Conditional mutant studies resolved that Mge1p promotes mt-Hsp70 cycling on translocating substrates by facilitating nucleotide-dependent substrate release, and that loss of this cycling leads to protein aggregation and incomplete folding inside mitochondria.\",\n      \"evidence\": \"Temperature-sensitive mge1 mutants with measurements of mt-Hsp70–preprotein binding, Hsp70–MIM44 dissociation, and protein aggregation in yeast mitochondria\",\n      \"pmids\": [\"7628446\", \"8524277\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether Mge1p directly contacts the translocon or acts solely through Hsp70 cycling was unresolved\",\n        \"Quantitative rate constants for ADP release not yet measured\"\n      ]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Reconstitution with purified components demonstrated that Mge1p stimulates mt-Hsp70 ATPase activity by accelerating ADP release rather than phosphate release, defining its precise biochemical step in the Hsp70 catalytic cycle.\",\n      \"evidence\": \"In vitro ATPase assay with purified recombinant mt-Hsp70 and Mge1p, phosphate inhibition experiments\",\n      \"pmids\": [\"9237899\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether the mechanism is conserved in mammalian GRPEL1 was not directly tested\",\n        \"Structural basis for ADP release stimulation unknown\"\n      ]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Discovery that mammals encode two mitochondrial GrpE paralogs (GRPEL1 and GRPEL2), both capable of binding mt-Hsp70 and stimulating its ATPase activity, raised the question of why two NEFs are maintained.\",\n      \"evidence\": \"DnaK affinity binding, ATP dissociation assay, ATPase stimulation with purified mammalian mt-Hsp70, cDNA cloning\",\n      \"pmids\": [\"9694873\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Functional specialization of GRPEL1 vs. GRPEL2 not addressed\",\n        \"Whether the two paralogs form a heterocomplex was unknown\"\n      ]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Biophysical characterization established that free GRPEL1 forms an elongated symmetric homodimer that undergoes conformational rearrangement to an asymmetric state upon DnaK/Hsp70 binding, providing the first structural insight into the mammalian NEF.\",\n      \"evidence\": \"Analytical ultracentrifugation, SAXS, circular dichroism, and differential scanning calorimetry of human GRPEL1\",\n      \"pmids\": [\"12840016\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"High-resolution atomic structure not available\",\n        \"Whether GRPEL1 functions as a heterodimer with GRPEL2 in vivo was unknown\"\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"The discovery that GRPEL1 and GRPEL2 form a hetero-oligomeric complex in human cells resolved the question of paralog specialization: the heterodimer is required for mutual stability and jointly regulates mtHsp70-dependent preprotein import and Fe-S cluster biogenesis, with GRPEL2 providing stress resistance and GRPEL1 acting as a stress modulator.\",\n      \"evidence\": \"Co-immunoprecipitation, RNAi knockdown, mitochondrial import and Fe-S biogenesis assays in human cells\",\n      \"pmids\": [\"28848044\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Stoichiometry and architecture of the heterodimer remain undefined\",\n        \"Whether heterodimer formation is regulated under stress conditions is unclear\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Dengue virus NS3 protease was shown to target GRPEL1 for proteolytic cleavage inside the mitochondrial matrix at two defined sites, establishing GRPEL1 destruction as a viral strategy to disrupt mitochondrial protein homeostasis.\",\n      \"evidence\": \"In vitro cleavage with purified NS3 protease, cleavage-site mutagenesis, mitochondrial import of NS3, Western blotting in virus-infected cells and severe dengue clinical samples\",\n      \"pmids\": [\"32581108\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether GRPEL2 is also cleaved by NS3 was not tested\",\n        \"Downstream consequences of GRPEL1 cleavage on Fe-S biogenesis and import in infected cells not measured\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Functional rescue experiments in neurons after subarachnoid hemorrhage demonstrated that loss of the GRPEL1–mtHsp70 complex leads to protein aggresome accumulation, mitochondrial depolarization, and caspase-9-dependent apoptosis, directly linking GRPEL1's NEF function to mitochondrial protein quality control and cell survival.\",\n      \"evidence\": \"GrpEL1 overexpression in primary neurons, co-IP, aggresome staining, JC-1 assay, ATP measurement, cleaved caspase-9 Western blot\",\n      \"pmids\": [\"35093469\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Findings from a single lab in one disease model; independent replication needed\",\n        \"Whether GRPEL2 compensates for GRPEL1 loss in this context was not addressed\",\n        \"Causal link between specific GRPEL1–mtHsp70 substrates and aggresome formation not established\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the high-resolution structure of the human GRPEL1–GRPEL2–mtHsp70 ternary complex, the mechanism governing heterodimer vs. homodimer assembly, and whether GRPEL1 plays roles in additional mitochondrial pathways beyond import and Fe-S cluster biogenesis.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No high-resolution structure of the human GRPEL1–mtHsp70 complex exists\",\n        \"Regulation of GRPEL1–GRPEL2 heterodimer assembly is unexplored\",\n        \"Complete substrate repertoire of GRPEL1-dependent mtHsp70 activity is unknown\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [6, 8, 11]},\n      {\"term_id\": \"GO:0044183\", \"supporting_discovery_ids\": [4, 5, 11, 13]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [0, 1, 2, 3, 7, 8, 11, 12]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0009536\", \"supporting_discovery_ids\": []},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [0, 2, 4, 5, 11]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [4, 5, 11, 13]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [12]}\n    ],\n    \"complexes\": [\n      \"GRPEL1–GRPEL2 hetero-oligomeric NEF complex\",\n      \"mtHsp70–GRPEL1/GRPEL2 chaperone complex\"\n    ],\n    \"partners\": [\n      \"HSPA9\",\n      \"GRPEL2\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}