{"gene":"EFL1","run_date":"2026-06-09T23:54:42","timeline":{"discoveries":[{"year":2013,"finding":"SBDS (yeast: Sdo1) acts as a guanine nucleotide exchange factor (GEF) for EFL1: in the presence of SBDS/Sdo1, the Km for GTP of EFL1 decreases approximately 2-fold while kcat remains unchanged, indicating that SBDS facilitates nucleotide exchange rather than stimulating hydrolysis.","method":"Steady-state kinetic analyses of GTP hydrolysis in vitro; circular dichroism and fluorescence-based assays with purified human and yeast EFL1 alone and in presence of SBDS/Sdo1","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro enzymatic kinetics with purified proteins, confirmed by two independent labs (PMID:23831625 and PMID:25991726 with more rigorous stopped-flow kinetics)","pmids":["23831625"],"is_preprint":false},{"year":2015,"finding":"SBDS acts as a guanine nucleotide exchange factor for EFL1 by dramatically increasing the GDP dissociation rate without altering GTP affinity, thereby promoting EFL1 activation. The SDS-associated S143L mutation in SBDS reduces its affinity for EFL1, impairing this nucleotide exchange regulation.","method":"Fluorescence stopped-flow spectroscopy with fluorescent guanine nucleotide analogs; fluorescence anisotropy measurements of EFL1–SBDS interaction with wild-type and S143L mutant SBDS","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — rigorous stopped-flow kinetics with multiple nucleotide binding steps characterized, mutagenesis of disease variant, and mechanistic model supported by quantitative kinetic data; replicates and extends PMID:23831625","pmids":["25991726"],"is_preprint":false},{"year":2014,"finding":"EFL1 directly interacts with SBDS; this interaction is mediated by the intrinsically disordered insertion domain of EFL1 (which adopts a more fixed conformation upon complex formation) and domains II–III of SBDS, as determined by ITC, size exclusion chromatography, and gel shift assays.","method":"Isothermal titration calorimetry (ITC), size exclusion chromatography, gel shift assay, circular dichroism spectroscopy using domain-truncated mutants of EFL1 and SBDS","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 1 / Moderate — multiple orthogonal biophysical methods (ITC, SEC, CD) with domain-truncation mutagenesis mapping the interaction interface","pmids":["24406167"],"is_preprint":false},{"year":2005,"finding":"Deletion of EFL1 in yeast results in heterogeneous rRNA conformations in the GTPase-associated center of free 60S subunits (domains II and VI of 25S rRNA), and EFL1 inhibits EF-2 GTPase activity, suggesting EFL1 and EF-2 share a ribosome-binding site. The rRNA conformational changes in Δefl1 60S subunits are attributable to nucleolar Tif6 deficit during 60S assembly.","method":"Chemical probing of rRNA conformation in wild-type, Δefl1, and dominant suppressor (R1) yeast strains; TAP-tag purification of Tif6-associated pre-60S ribosomes; EF-2 GTPase activity assay in the presence/absence of EFL1","journal":"Journal of molecular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic and biochemical approaches in yeast (rRNA footprinting, GTPase inhibition assay, TAP purification) in a single study with multiple methods","pmids":["16095611"],"is_preprint":false},{"year":2017,"finding":"Pathogenic missense mutations in EFL1 (p.R1095Q and p.M882K) do not affect EFL1 GTPase activity or its stimulation by SBDS, but abolish the ability of EFL1 to promote cytoplasmic release of eIF6 (Tif6) from the 60S subunit, as shown by mislocalization of Tif6-GFP to the cytoplasm in yeast expressing the mutant proteins.","method":"Green malachite colorimetric GTPase assay; fluorescence microscopy of Tif6-GFP localization in complemented efl1Δ yeast; circular dichroism and SAXS of mutant EFL1 proteins; yeast growth complementation assay","journal":"Journal of medical genetics","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — multiple orthogonal methods (GTPase assay, live fluorescence microscopy, SAXS, complementation) in a single study establishing mechanistic consequence of patient mutations","pmids":["28331068"],"is_preprint":false},{"year":2019,"finding":"Biallelic loss-of-function mutations in EFL1 in human patients cause defective eIF6 eviction from 60S ribosomal subunits, impaired ribosomal subunit joining, and attenuated global protein translation. In mice, Efl1 deficiency recapitulates key SDS phenotypes.","method":"Patient-derived cell studies: ribosomal subunit joining assays, global translation assays (polysome profiling); Efl1 knockout mouse model phenotyping","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (subunit joining, polysome profiling, mouse KO model) across three independent patient families, mechanistically linking EFL1 to eIF6 release and translation","pmids":["31151987"],"is_preprint":false},{"year":2019,"finding":"Sdo1 (yeast SBDS) and guanine nucleotides exert cooperative allosteric effects on Efl1 conformational landscape in solution, modulating Efl1 in a way consistent with GTPase activation, as characterized by calorimetric binding analysis. EFL1 in solution adopts an inverted orientation relative to the 60S-bound cryo-EM conformation.","method":"Isothermal titration calorimetry (ITC) characterizing Efl1 interactions with GDP, GTP, and Sdo1 separately and in combination; structural-based energetic analysis","journal":"Biophysical chemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — rigorous calorimetric method but single lab, single method, results are interpretive/model-building","pmids":["30780079"],"is_preprint":false},{"year":2019,"finding":"Molecular dynamics simulations supported by SAXS reveal that SDS-associated EFL1 mutations (T127A, M882K, R1095Q) cause a distinctive rotation of domain IV relative to domains I and II, suggesting EFL1 function is governed by an allosteric mechanism involving the concerted action of the GTPase domain (domain I) and domain IV.","method":"Comparative molecular dynamics simulations on wild-type and three mutant EFL1 proteins, validated by small-angle X-ray scattering (SAXS) experiments","journal":"Journal of biomolecular structure & dynamics","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — SAXS provides experimental validation but the mechanistic interpretation relies heavily on computational MD; single lab","pmids":["31838967"],"is_preprint":false},{"year":2022,"finding":"The SDS-associated EFL1 R1095Q mutation (R1086Q in yeast) disrupts a long-distance intramolecular network such that Sdo1 and guanine nucleotides no longer elicit the conformational changes required for eIF6 release, without altering steady-state GTPase kinetics.","method":"Enzyme kinetics assays; isothermal titration calorimetry of nucleotide and Sdo1 binding to wild-type vs. R1086Q Efl1; conformational analysis","journal":"Biomolecules","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro biochemical and calorimetric methods on purified proteins; single lab, mechanistic model supported by multiple methods but limited to one mutant","pmids":["36009035"],"is_preprint":false},{"year":2021,"finding":"EFL1 proteins are exclusive to eukaryotes and originated by gene duplication from EF-2 proteins, specializing in ribosome maturation. Functional complementation assays show species-specific cooperation: no EFL1 orthologue or cross-species EFL1•SBDS combination could rescue the function of the corresponding yeast EFL1•SBDS pair. SBDS domain 2 is vital for function with EFL1 and the 60S subunit.","method":"Phylogenetic analysis; GTPase activity assays with orthologous EFL1 proteins; yeast complementation assays with orthologous and chimeric EFL1 and SBDS proteins","journal":"Molecular genetics and genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional complementation and GTPase assays across multiple species; single lab with orthogonal genetic and biochemical methods","pmids":["34453201"],"is_preprint":false},{"year":2021,"finding":"Loss of EFL1 specifically impairs assembly of 80S ribosomes on terminal oligopyrimidine (TOP) element-containing ribosomal protein transcripts, demonstrating a role for EFL1 in translational control of this specific mRNA class.","method":"Cell line and animal models with EFL1 loss; 80S ribosome assembly assays on TOP-element containing transcripts","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — specific mechanistic finding (TOP mRNA translation) from a single study in cell lines and animal models; single lab","pmids":["34115847"],"is_preprint":false},{"year":2014,"finding":"Knockdown of EFTUD1 (EFL1) in glioma cell lines impairs ribosome biogenesis, induces G1 cell-cycle arrest and apoptosis, and triggers protective autophagy as an adaptive response.","method":"siRNA knockdown of EFTUD1 in glioma cell lines; Western blot; cell cycle analysis; apoptosis and autophagy assays; autophagy inhibitor (chloroquine) combination experiments","journal":"Neuro-oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — clean KD with defined cellular phenotypes (G1 arrest, apoptosis, autophagy) and mechanistic link to ribosome biogenesis; single lab, single study","pmids":["25015090"],"is_preprint":false},{"year":2026,"finding":"X-ray hydroxyl radical footprinting of yeast Efl1 R1086Q (equivalent to human R1095Q) reveals widespread conformational changes across the protein despite the mutation being located in domain IV, particularly affecting domain I, demonstrating long-range intramolecular communication. A compensatory second-site mutation in the allosteric pathway rescued growth defects and restored nuclear localization of Tif6, confirming that R1086Q disrupts a structural communication network spanning from the nucleotide-binding pocket to domain IV.","method":"X-ray hydroxyl radical footprinting (synchrotron-based); yeast growth complementation with second-site suppressor mutations; fluorescence microscopy of Tif6-GFP nuclear localization","journal":"Protein science","confidence":"High","confidence_rationale":"Tier 1 / Moderate — synchrotron hydroxyl radical footprinting combined with genetic suppressor rescue and live-cell fluorescence localization; multiple orthogonal methods in single study establishing allosteric mechanism","pmids":["41848393"],"is_preprint":false}],"current_model":"EFL1 is a eukaryote-specific GTPase that functions in the final cytoplasmic maturation step of the 60S ribosomal subunit by cooperating with SBDS to catalyze the release of the anti-association factor eIF6, thereby licensing the large subunit to enter translation; SBDS acts as a guanine nucleotide exchange factor for EFL1 by accelerating GDP dissociation, and EFL1 function is governed by an allosteric communication network linking its GTPase domain (domain I) to domain IV, disruption of which by SDS-associated mutations impairs conformational changes required for eIF6 eviction without necessarily abolishing GTPase activity."},"narrative":{"mechanistic_narrative":"EFL1 is a eukaryote-specific GTPase that catalyzes the final cytoplasmic maturation step of the 60S ribosomal subunit, cooperating with SBDS to drive release of the anti-association factor eIF6 (yeast Tif6) and thereby license the large subunit for translation [PMID:28331068, PMID:31151987]. SBDS functions as a guanine nucleotide exchange factor for EFL1, dramatically accelerating GDP dissociation without altering GTP affinity or hydrolysis rate, which promotes EFL1 activation; the disease-associated SBDS S143L substitution weakens its affinity for EFL1 and impairs this exchange [PMID:23831625, PMID:25991726], an interaction mediated by the intrinsically disordered insertion domain of EFL1 and domains II–III of SBDS [PMID:24406167]. In human patients, biallelic loss-of-function EFL1 mutations cause defective eIF6 eviction, impaired subunit joining, and attenuated global translation, with Efl1-deficient mice recapitulating Shwachman-Diamond syndrome phenotypes [PMID:31151987]; loss of EFL1 selectively impairs 80S assembly on TOP-element ribosomal protein transcripts, linking it to translational control of this mRNA class [PMID:34115847]. A central mechanistic theme is allosteric control: SDS-associated missense mutations such as R1095Q and M882K leave steady-state GTPase activity and SBDS stimulation intact yet abolish the conformational changes required for eIF6 release [PMID:28331068, PMID:36009035], acting through a long-range intramolecular communication network connecting the GTPase domain (domain I) to domain IV whose disruption is rescued by second-site suppressors in the same allosteric pathway [PMID:31838967, PMID:41848393].","teleology":[{"year":2005,"claim":"Established a functional link between EFL1 and 60S maturation by showing its loss perturbs the GTPase-associated center of the large subunit and that it competes with the elongation machinery for a shared ribosome-binding site.","evidence":"rRNA chemical probing, TAP purification of Tif6-pre-60S, and EF-2 GTPase inhibition assays in wild-type and Δefl1 yeast","pmids":["16095611"],"confidence":"Medium","gaps":["Did not define the catalytic event EFL1 performs on the subunit","Causal role of Tif6/eIF6 in the rRNA defect inferred indirectly","No human protein characterized"]},{"year":2013,"claim":"Resolved how SBDS regulates EFL1 enzymatically by demonstrating it acts as a GEF rather than a GTPase-activating partner, lowering the Km for GTP without changing kcat.","evidence":"Steady-state kinetic analyses of GTP hydrolysis with purified human and yeast EFL1 ± SBDS/Sdo1","pmids":["23831625"],"confidence":"High","gaps":["Did not directly measure nucleotide exchange rates","Did not connect GEF activity to eIF6 release"]},{"year":2014,"claim":"Mapped the physical EFL1–SBDS interface, showing the EFL1 disordered insertion domain and SBDS domains II–III mediate complex formation with coupled folding.","evidence":"ITC, size exclusion chromatography, gel shift, and CD with domain-truncated EFL1 and SBDS","pmids":["24406167"],"confidence":"High","gaps":["Interface mapped by truncation, not residue-resolution structure","Functional consequence of insertion-domain folding not established"]},{"year":2015,"claim":"Defined the kinetic mechanism of SBDS as a GEF, showing it accelerates GDP dissociation specifically, and linked a disease variant to defective EFL1 binding.","evidence":"Stopped-flow spectroscopy with fluorescent nucleotide analogs and anisotropy of WT vs S143L SBDS binding EFL1","pmids":["25991726"],"confidence":"High","gaps":["Did not address how exchange couples to subunit binding","S143L effect on eIF6 release not directly tested"]},{"year":2017,"claim":"Dissociated GTPase activity from biological function, showing patient mutations preserve catalysis and SBDS stimulation yet block eIF6 eviction from the 60S subunit.","evidence":"GTPase colorimetric assay, Tif6-GFP localization microscopy, CD/SAXS, and yeast complementation of mutant EFL1","pmids":["28331068"],"confidence":"High","gaps":["Molecular basis of how eviction is uncoupled from GTP turnover unknown","Structural model of the active conformation lacking"]},{"year":2019,"claim":"Confirmed in humans and mice that EFL1 loss-of-function causes defective eIF6 release, impaired subunit joining, and reduced translation, establishing EFL1 as a Shwachman-Diamond-syndrome gene.","evidence":"Patient-cell subunit-joining and polysome assays plus Efl1 knockout mouse phenotyping across three families","pmids":["31151987"],"confidence":"High","gaps":["Tissue-specific bases of phenotype not resolved","Did not define which transcripts are most translationally affected"]},{"year":2019,"claim":"Characterized the allosteric coupling of Sdo1 and guanine nucleotides on EFL1's conformational landscape and noted the solution conformation differs from the 60S-bound state.","evidence":"ITC of Efl1 with GDP, GTP, and Sdo1 separately and combined, with structure-based energetic analysis","pmids":["30780079"],"confidence":"Medium","gaps":["Interpretive/model-building from a single method and lab","Functional readout of the conformational change not assayed"]},{"year":2019,"claim":"Localized the structural defect of SDS mutations to a rotation of domain IV relative to domains I/II, implicating concerted GTPase-domain/domain-IV action.","evidence":"Molecular dynamics simulations of WT and three mutant EFL1 proteins validated by SAXS","pmids":["31838967"],"confidence":"Medium","gaps":["Mechanistic interpretation relies heavily on computation","Single lab; high-resolution structure of mutants absent"]},{"year":2021,"claim":"Placed EFL1 evolutionarily as an EF-2 duplicate specialized for ribosome maturation and showed EFL1•SBDS cooperation is species-specific and non-interchangeable.","evidence":"Phylogenetics, GTPase assays of orthologues, and yeast complementation with orthologous/chimeric EFL1 and SBDS","pmids":["34453201"],"confidence":"Medium","gaps":["Structural basis of species specificity unresolved","Role of SBDS domain 2 mechanistically undefined"]},{"year":2021,"claim":"Identified a specialized translational role, showing EFL1 loss selectively impairs 80S assembly on TOP-element ribosomal protein mRNAs.","evidence":"80S assembly assays on TOP-containing transcripts in EFL1-loss cell and animal models","pmids":["34115847"],"confidence":"Medium","gaps":["Mechanism of TOP-transcript selectivity unknown","Single lab/single study"]},{"year":2014,"claim":"Linked EFL1 (EFTUD1) depletion to cellular consequences of disrupted ribosome biogenesis, including G1 arrest, apoptosis, and protective autophagy in glioma cells.","evidence":"siRNA knockdown with cell-cycle, apoptosis, autophagy assays and chloroquine combination in glioma lines","pmids":["25015090"],"confidence":"Medium","gaps":["Causality between specific maturation defect and phenotype not isolated","Single cell-type context"]},{"year":2022,"claim":"Demonstrated that the R1095Q/R1086Q mutation disrupts a long-distance intramolecular network so Sdo1 and nucleotides no longer trigger eIF6-release conformations, without affecting GTPase kinetics.","evidence":"Enzyme kinetics, ITC of nucleotide and Sdo1 binding, and conformational analysis of WT vs R1086Q Efl1","pmids":["36009035"],"confidence":"Medium","gaps":["Limited to one mutant","Topology of the communication network not yet mapped experimentally"]},{"year":2026,"claim":"Mapped the allosteric communication network experimentally, showing the domain-IV R1086Q mutation propagates changes to domain I and the nucleotide pocket, and that a second-site suppressor in the pathway rescues function.","evidence":"X-ray hydroxyl radical footprinting, yeast growth complementation with suppressor mutations, and Tif6-GFP localization","pmids":["41848393"],"confidence":"High","gaps":["Atomic-resolution structure of the active and mutant states still lacking","How the network couples to eIF6 displacement on the ribosome unresolved"]},{"year":null,"claim":"How EFL1's GTP cycle, allosteric domain-IV motion, and SBDS GEF activity are mechanically coupled to physical eviction of eIF6 from the 60S subunit, and the structural basis of TOP-mRNA selectivity, remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No high-resolution structure of the active EFL1•SBDS•60S•eIF6 transition state","Mechanism linking conformational change to eIF6 release undefined","Basis of TOP-transcript specificity unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003924","term_label":"GTPase activity","supporting_discovery_ids":[0,1,3,4,9]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[4,8,12]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[4]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[4,5,10]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[5,10]}],"complexes":["pre-60S ribosomal particle"],"partners":["SBDS","EIF6"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q7Z2Z2","full_name":"Elongation factor-like GTPase 1","aliases":["Elongation factor Tu GTP-binding domain-containing protein 1","Elongation factor-like 1","Protein FAM42A"],"length_aa":1120,"mass_kda":125.4,"function":"GTPase involved in the biogenesis of the 60S ribosomal subunit and translational activation of ribosomes. Together with SBDS, triggers the GTP-dependent release of EIF6 from 60S pre-ribosomes in the cytoplasm, thereby activating ribosomes for translation competence by allowing 80S ribosome assembly and facilitating EIF6 recycling to the nucleus, where it is required for 60S rRNA processing and nuclear export","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/Q7Z2Z2/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/EFL1","classification":"Common Essential","n_dependent_lines":1159,"n_total_lines":1208,"dependency_fraction":0.9594370860927153},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/EFL1","total_profiled":1310},"omim":[{"mim_id":"617941","title":"SHWACHMAN-DIAMOND SYNDROME 2; SDS2","url":"https://www.omim.org/entry/617941"},{"mim_id":"617538","title":"ELONGATION FACTOR-LIKE GTPase 1; EFL1","url":"https://www.omim.org/entry/617538"},{"mim_id":"607444","title":"SBDS RIBOSOME MATURATION FACTOR; SBDS","url":"https://www.omim.org/entry/607444"},{"mim_id":"260400","title":"SHWACHMAN-DIAMOND SYNDROME 1; SDS1","url":"https://www.omim.org/entry/260400"},{"mim_id":"191164","title":"EPHRIN A1; EFNA1","url":"https://www.omim.org/entry/191164"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/EFL1"},"hgnc":{"alias_symbol":["FLJ13119","FAM42A","HsT19294","RIA1"],"prev_symbol":["EFTUD1"]},"alphafold":{"accession":"Q7Z2Z2","domains":[{"cath_id":"3.40.50.300","chopping":"2-190_225-241_351-367","consensus_level":"medium","plddt":85.2918,"start":2,"end":367},{"cath_id":"3.90.1430.10","chopping":"245-350","consensus_level":"medium","plddt":80.7482,"start":245,"end":350},{"cath_id":"2.40.30.10","chopping":"372-424_502-539_548-600","consensus_level":"medium","plddt":79.141,"start":372,"end":600},{"cath_id":"3.30.70.870","chopping":"619-690","consensus_level":"medium","plddt":87.6887,"start":619,"end":690},{"cath_id":"3.30.230.10","chopping":"712-786_798-901_958-976","consensus_level":"high","plddt":74.6295,"start":712,"end":976},{"cath_id":"3.30.70.240","chopping":"982-1063","consensus_level":"medium","plddt":81.5055,"start":982,"end":1063}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q7Z2Z2","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q7Z2Z2-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q7Z2Z2-F1-predicted_aligned_error_v6.png","plddt_mean":74.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=EFL1","jax_strain_url":"https://www.jax.org/strain/search?query=EFL1"},"sequence":{"accession":"Q7Z2Z2","fasta_url":"https://rest.uniprot.org/uniprotkb/Q7Z2Z2.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q7Z2Z2/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q7Z2Z2"}},"corpus_meta":[{"pmid":"11463372","id":"PMC_11463372","title":"dpl-1 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GTPase.","date":"2022","source":"Biomolecules","url":"https://pubmed.ncbi.nlm.nih.gov/36009035","citation_count":2,"is_preprint":false},{"pmid":"34453201","id":"PMC_34453201","title":"Evolutionary and functional relationships in the ribosome biogenesis SBDS and EFL1 protein families.","date":"2021","source":"Molecular genetics and genomics : MGG","url":"https://pubmed.ncbi.nlm.nih.gov/34453201","citation_count":1,"is_preprint":false},{"pmid":"41848393","id":"PMC_41848393","title":"Hydroxyl radical footprinting modification reveals an intradomain communication pathway in EFL1 disrupted by a Shwachman-Diamond syndrome-associated mutation.","date":"2026","source":"Protein science : a publication of the Protein Society","url":"https://pubmed.ncbi.nlm.nih.gov/41848393","citation_count":0,"is_preprint":false},{"pmid":"42043893","id":"PMC_42043893","title":"Homozygous Pathogenic Variant in Elongation Factor-Like 1 (EFL1) as a Causal Factor in Shwachman-Diamond Syndrome 2 in a Palestinian Child, With Distinct Ocular Manifestations.","date":"2026","source":"Molecular genetics & genomic medicine","url":"https://pubmed.ncbi.nlm.nih.gov/42043893","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":11256,"output_tokens":3506,"usd":0.043179,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11138,"output_tokens":3933,"usd":0.077008,"stage2_stop_reason":"end_turn"},"total_usd":0.120187,"stage1_batch_id":"msgbatch_01AsR7g8dGTEiEw9U83bJeWn","stage2_batch_id":"msgbatch_01YV5ZyxtFNUZEjxRcpd9jzb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2013,\n      \"finding\": \"SBDS (yeast: Sdo1) acts as a guanine nucleotide exchange factor (GEF) for EFL1: in the presence of SBDS/Sdo1, the Km for GTP of EFL1 decreases approximately 2-fold while kcat remains unchanged, indicating that SBDS facilitates nucleotide exchange rather than stimulating hydrolysis.\",\n      \"method\": \"Steady-state kinetic analyses of GTP hydrolysis in vitro; circular dichroism and fluorescence-based assays with purified human and yeast EFL1 alone and in presence of SBDS/Sdo1\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro enzymatic kinetics with purified proteins, confirmed by two independent labs (PMID:23831625 and PMID:25991726 with more rigorous stopped-flow kinetics)\",\n      \"pmids\": [\"23831625\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"SBDS acts as a guanine nucleotide exchange factor for EFL1 by dramatically increasing the GDP dissociation rate without altering GTP affinity, thereby promoting EFL1 activation. The SDS-associated S143L mutation in SBDS reduces its affinity for EFL1, impairing this nucleotide exchange regulation.\",\n      \"method\": \"Fluorescence stopped-flow spectroscopy with fluorescent guanine nucleotide analogs; fluorescence anisotropy measurements of EFL1–SBDS interaction with wild-type and S143L mutant SBDS\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — rigorous stopped-flow kinetics with multiple nucleotide binding steps characterized, mutagenesis of disease variant, and mechanistic model supported by quantitative kinetic data; replicates and extends PMID:23831625\",\n      \"pmids\": [\"25991726\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"EFL1 directly interacts with SBDS; this interaction is mediated by the intrinsically disordered insertion domain of EFL1 (which adopts a more fixed conformation upon complex formation) and domains II–III of SBDS, as determined by ITC, size exclusion chromatography, and gel shift assays.\",\n      \"method\": \"Isothermal titration calorimetry (ITC), size exclusion chromatography, gel shift assay, circular dichroism spectroscopy using domain-truncated mutants of EFL1 and SBDS\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — multiple orthogonal biophysical methods (ITC, SEC, CD) with domain-truncation mutagenesis mapping the interaction interface\",\n      \"pmids\": [\"24406167\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Deletion of EFL1 in yeast results in heterogeneous rRNA conformations in the GTPase-associated center of free 60S subunits (domains II and VI of 25S rRNA), and EFL1 inhibits EF-2 GTPase activity, suggesting EFL1 and EF-2 share a ribosome-binding site. The rRNA conformational changes in Δefl1 60S subunits are attributable to nucleolar Tif6 deficit during 60S assembly.\",\n      \"method\": \"Chemical probing of rRNA conformation in wild-type, Δefl1, and dominant suppressor (R1) yeast strains; TAP-tag purification of Tif6-associated pre-60S ribosomes; EF-2 GTPase activity assay in the presence/absence of EFL1\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic and biochemical approaches in yeast (rRNA footprinting, GTPase inhibition assay, TAP purification) in a single study with multiple methods\",\n      \"pmids\": [\"16095611\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Pathogenic missense mutations in EFL1 (p.R1095Q and p.M882K) do not affect EFL1 GTPase activity or its stimulation by SBDS, but abolish the ability of EFL1 to promote cytoplasmic release of eIF6 (Tif6) from the 60S subunit, as shown by mislocalization of Tif6-GFP to the cytoplasm in yeast expressing the mutant proteins.\",\n      \"method\": \"Green malachite colorimetric GTPase assay; fluorescence microscopy of Tif6-GFP localization in complemented efl1Δ yeast; circular dichroism and SAXS of mutant EFL1 proteins; yeast growth complementation assay\",\n      \"journal\": \"Journal of medical genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — multiple orthogonal methods (GTPase assay, live fluorescence microscopy, SAXS, complementation) in a single study establishing mechanistic consequence of patient mutations\",\n      \"pmids\": [\"28331068\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Biallelic loss-of-function mutations in EFL1 in human patients cause defective eIF6 eviction from 60S ribosomal subunits, impaired ribosomal subunit joining, and attenuated global protein translation. In mice, Efl1 deficiency recapitulates key SDS phenotypes.\",\n      \"method\": \"Patient-derived cell studies: ribosomal subunit joining assays, global translation assays (polysome profiling); Efl1 knockout mouse model phenotyping\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (subunit joining, polysome profiling, mouse KO model) across three independent patient families, mechanistically linking EFL1 to eIF6 release and translation\",\n      \"pmids\": [\"31151987\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Sdo1 (yeast SBDS) and guanine nucleotides exert cooperative allosteric effects on Efl1 conformational landscape in solution, modulating Efl1 in a way consistent with GTPase activation, as characterized by calorimetric binding analysis. EFL1 in solution adopts an inverted orientation relative to the 60S-bound cryo-EM conformation.\",\n      \"method\": \"Isothermal titration calorimetry (ITC) characterizing Efl1 interactions with GDP, GTP, and Sdo1 separately and in combination; structural-based energetic analysis\",\n      \"journal\": \"Biophysical chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — rigorous calorimetric method but single lab, single method, results are interpretive/model-building\",\n      \"pmids\": [\"30780079\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Molecular dynamics simulations supported by SAXS reveal that SDS-associated EFL1 mutations (T127A, M882K, R1095Q) cause a distinctive rotation of domain IV relative to domains I and II, suggesting EFL1 function is governed by an allosteric mechanism involving the concerted action of the GTPase domain (domain I) and domain IV.\",\n      \"method\": \"Comparative molecular dynamics simulations on wild-type and three mutant EFL1 proteins, validated by small-angle X-ray scattering (SAXS) experiments\",\n      \"journal\": \"Journal of biomolecular structure & dynamics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — SAXS provides experimental validation but the mechanistic interpretation relies heavily on computational MD; single lab\",\n      \"pmids\": [\"31838967\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"The SDS-associated EFL1 R1095Q mutation (R1086Q in yeast) disrupts a long-distance intramolecular network such that Sdo1 and guanine nucleotides no longer elicit the conformational changes required for eIF6 release, without altering steady-state GTPase kinetics.\",\n      \"method\": \"Enzyme kinetics assays; isothermal titration calorimetry of nucleotide and Sdo1 binding to wild-type vs. R1086Q Efl1; conformational analysis\",\n      \"journal\": \"Biomolecules\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro biochemical and calorimetric methods on purified proteins; single lab, mechanistic model supported by multiple methods but limited to one mutant\",\n      \"pmids\": [\"36009035\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"EFL1 proteins are exclusive to eukaryotes and originated by gene duplication from EF-2 proteins, specializing in ribosome maturation. Functional complementation assays show species-specific cooperation: no EFL1 orthologue or cross-species EFL1•SBDS combination could rescue the function of the corresponding yeast EFL1•SBDS pair. SBDS domain 2 is vital for function with EFL1 and the 60S subunit.\",\n      \"method\": \"Phylogenetic analysis; GTPase activity assays with orthologous EFL1 proteins; yeast complementation assays with orthologous and chimeric EFL1 and SBDS proteins\",\n      \"journal\": \"Molecular genetics and genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional complementation and GTPase assays across multiple species; single lab with orthogonal genetic and biochemical methods\",\n      \"pmids\": [\"34453201\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Loss of EFL1 specifically impairs assembly of 80S ribosomes on terminal oligopyrimidine (TOP) element-containing ribosomal protein transcripts, demonstrating a role for EFL1 in translational control of this specific mRNA class.\",\n      \"method\": \"Cell line and animal models with EFL1 loss; 80S ribosome assembly assays on TOP-element containing transcripts\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — specific mechanistic finding (TOP mRNA translation) from a single study in cell lines and animal models; single lab\",\n      \"pmids\": [\"34115847\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Knockdown of EFTUD1 (EFL1) in glioma cell lines impairs ribosome biogenesis, induces G1 cell-cycle arrest and apoptosis, and triggers protective autophagy as an adaptive response.\",\n      \"method\": \"siRNA knockdown of EFTUD1 in glioma cell lines; Western blot; cell cycle analysis; apoptosis and autophagy assays; autophagy inhibitor (chloroquine) combination experiments\",\n      \"journal\": \"Neuro-oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — clean KD with defined cellular phenotypes (G1 arrest, apoptosis, autophagy) and mechanistic link to ribosome biogenesis; single lab, single study\",\n      \"pmids\": [\"25015090\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"X-ray hydroxyl radical footprinting of yeast Efl1 R1086Q (equivalent to human R1095Q) reveals widespread conformational changes across the protein despite the mutation being located in domain IV, particularly affecting domain I, demonstrating long-range intramolecular communication. A compensatory second-site mutation in the allosteric pathway rescued growth defects and restored nuclear localization of Tif6, confirming that R1086Q disrupts a structural communication network spanning from the nucleotide-binding pocket to domain IV.\",\n      \"method\": \"X-ray hydroxyl radical footprinting (synchrotron-based); yeast growth complementation with second-site suppressor mutations; fluorescence microscopy of Tif6-GFP nuclear localization\",\n      \"journal\": \"Protein science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — synchrotron hydroxyl radical footprinting combined with genetic suppressor rescue and live-cell fluorescence localization; multiple orthogonal methods in single study establishing allosteric mechanism\",\n      \"pmids\": [\"41848393\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"EFL1 is a eukaryote-specific GTPase that functions in the final cytoplasmic maturation step of the 60S ribosomal subunit by cooperating with SBDS to catalyze the release of the anti-association factor eIF6, thereby licensing the large subunit to enter translation; SBDS acts as a guanine nucleotide exchange factor for EFL1 by accelerating GDP dissociation, and EFL1 function is governed by an allosteric communication network linking its GTPase domain (domain I) to domain IV, disruption of which by SDS-associated mutations impairs conformational changes required for eIF6 eviction without necessarily abolishing GTPase activity.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"EFL1 is a eukaryote-specific GTPase that catalyzes the final cytoplasmic maturation step of the 60S ribosomal subunit, cooperating with SBDS to drive release of the anti-association factor eIF6 (yeast Tif6) and thereby license the large subunit for translation [#4, #5]. SBDS functions as a guanine nucleotide exchange factor for EFL1, dramatically accelerating GDP dissociation without altering GTP affinity or hydrolysis rate, which promotes EFL1 activation; the disease-associated SBDS S143L substitution weakens its affinity for EFL1 and impairs this exchange [#0, #1], an interaction mediated by the intrinsically disordered insertion domain of EFL1 and domains II–III of SBDS [#2]. In human patients, biallelic loss-of-function EFL1 mutations cause defective eIF6 eviction, impaired subunit joining, and attenuated global translation, with Efl1-deficient mice recapitulating Shwachman-Diamond syndrome phenotypes [#5]; loss of EFL1 selectively impairs 80S assembly on TOP-element ribosomal protein transcripts, linking it to translational control of this mRNA class [#10]. A central mechanistic theme is allosteric control: SDS-associated missense mutations such as R1095Q and M882K leave steady-state GTPase activity and SBDS stimulation intact yet abolish the conformational changes required for eIF6 release [#4, #8], acting through a long-range intramolecular communication network connecting the GTPase domain (domain I) to domain IV whose disruption is rescued by second-site suppressors in the same allosteric pathway [#7, #12].\",\n  \"teleology\": [\n    {\n      \"year\": 2005,\n      \"claim\": \"Established a functional link between EFL1 and 60S maturation by showing its loss perturbs the GTPase-associated center of the large subunit and that it competes with the elongation machinery for a shared ribosome-binding site.\",\n      \"evidence\": \"rRNA chemical probing, TAP purification of Tif6-pre-60S, and EF-2 GTPase inhibition assays in wild-type and Δefl1 yeast\",\n      \"pmids\": [\"16095611\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not define the catalytic event EFL1 performs on the subunit\", \"Causal role of Tif6/eIF6 in the rRNA defect inferred indirectly\", \"No human protein characterized\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Resolved how SBDS regulates EFL1 enzymatically by demonstrating it acts as a GEF rather than a GTPase-activating partner, lowering the Km for GTP without changing kcat.\",\n      \"evidence\": \"Steady-state kinetic analyses of GTP hydrolysis with purified human and yeast EFL1 ± SBDS/Sdo1\",\n      \"pmids\": [\"23831625\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not directly measure nucleotide exchange rates\", \"Did not connect GEF activity to eIF6 release\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Mapped the physical EFL1–SBDS interface, showing the EFL1 disordered insertion domain and SBDS domains II–III mediate complex formation with coupled folding.\",\n      \"evidence\": \"ITC, size exclusion chromatography, gel shift, and CD with domain-truncated EFL1 and SBDS\",\n      \"pmids\": [\"24406167\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Interface mapped by truncation, not residue-resolution structure\", \"Functional consequence of insertion-domain folding not established\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defined the kinetic mechanism of SBDS as a GEF, showing it accelerates GDP dissociation specifically, and linked a disease variant to defective EFL1 binding.\",\n      \"evidence\": \"Stopped-flow spectroscopy with fluorescent nucleotide analogs and anisotropy of WT vs S143L SBDS binding EFL1\",\n      \"pmids\": [\"25991726\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not address how exchange couples to subunit binding\", \"S143L effect on eIF6 release not directly tested\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Dissociated GTPase activity from biological function, showing patient mutations preserve catalysis and SBDS stimulation yet block eIF6 eviction from the 60S subunit.\",\n      \"evidence\": \"GTPase colorimetric assay, Tif6-GFP localization microscopy, CD/SAXS, and yeast complementation of mutant EFL1\",\n      \"pmids\": [\"28331068\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of how eviction is uncoupled from GTP turnover unknown\", \"Structural model of the active conformation lacking\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Confirmed in humans and mice that EFL1 loss-of-function causes defective eIF6 release, impaired subunit joining, and reduced translation, establishing EFL1 as a Shwachman-Diamond-syndrome gene.\",\n      \"evidence\": \"Patient-cell subunit-joining and polysome assays plus Efl1 knockout mouse phenotyping across three families\",\n      \"pmids\": [\"31151987\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Tissue-specific bases of phenotype not resolved\", \"Did not define which transcripts are most translationally affected\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Characterized the allosteric coupling of Sdo1 and guanine nucleotides on EFL1's conformational landscape and noted the solution conformation differs from the 60S-bound state.\",\n      \"evidence\": \"ITC of Efl1 with GDP, GTP, and Sdo1 separately and combined, with structure-based energetic analysis\",\n      \"pmids\": [\"30780079\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Interpretive/model-building from a single method and lab\", \"Functional readout of the conformational change not assayed\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Localized the structural defect of SDS mutations to a rotation of domain IV relative to domains I/II, implicating concerted GTPase-domain/domain-IV action.\",\n      \"evidence\": \"Molecular dynamics simulations of WT and three mutant EFL1 proteins validated by SAXS\",\n      \"pmids\": [\"31838967\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic interpretation relies heavily on computation\", \"Single lab; high-resolution structure of mutants absent\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Placed EFL1 evolutionarily as an EF-2 duplicate specialized for ribosome maturation and showed EFL1•SBDS cooperation is species-specific and non-interchangeable.\",\n      \"evidence\": \"Phylogenetics, GTPase assays of orthologues, and yeast complementation with orthologous/chimeric EFL1 and SBDS\",\n      \"pmids\": [\"34453201\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of species specificity unresolved\", \"Role of SBDS domain 2 mechanistically undefined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified a specialized translational role, showing EFL1 loss selectively impairs 80S assembly on TOP-element ribosomal protein mRNAs.\",\n      \"evidence\": \"80S assembly assays on TOP-containing transcripts in EFL1-loss cell and animal models\",\n      \"pmids\": [\"34115847\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of TOP-transcript selectivity unknown\", \"Single lab/single study\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Linked EFL1 (EFTUD1) depletion to cellular consequences of disrupted ribosome biogenesis, including G1 arrest, apoptosis, and protective autophagy in glioma cells.\",\n      \"evidence\": \"siRNA knockdown with cell-cycle, apoptosis, autophagy assays and chloroquine combination in glioma lines\",\n      \"pmids\": [\"25015090\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causality between specific maturation defect and phenotype not isolated\", \"Single cell-type context\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Demonstrated that the R1095Q/R1086Q mutation disrupts a long-distance intramolecular network so Sdo1 and nucleotides no longer trigger eIF6-release conformations, without affecting GTPase kinetics.\",\n      \"evidence\": \"Enzyme kinetics, ITC of nucleotide and Sdo1 binding, and conformational analysis of WT vs R1086Q Efl1\",\n      \"pmids\": [\"36009035\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Limited to one mutant\", \"Topology of the communication network not yet mapped experimentally\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Mapped the allosteric communication network experimentally, showing the domain-IV R1086Q mutation propagates changes to domain I and the nucleotide pocket, and that a second-site suppressor in the pathway rescues function.\",\n      \"evidence\": \"X-ray hydroxyl radical footprinting, yeast growth complementation with suppressor mutations, and Tif6-GFP localization\",\n      \"pmids\": [\"41848393\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Atomic-resolution structure of the active and mutant states still lacking\", \"How the network couples to eIF6 displacement on the ribosome unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How EFL1's GTP cycle, allosteric domain-IV motion, and SBDS GEF activity are mechanically coupled to physical eviction of eIF6 from the 60S subunit, and the structural basis of TOP-mRNA selectivity, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No high-resolution structure of the active EFL1•SBDS•60S•eIF6 transition state\", \"Mechanism linking conformational change to eIF6 release undefined\", \"Basis of TOP-transcript specificity unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003924\", \"supporting_discovery_ids\": [0, 1, 3, 4, 9]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [4, 8, 12]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [4, 5, 10]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [5, 10]}\n    ],\n    \"complexes\": [\"pre-60S ribosomal particle\"],\n    \"partners\": [\"SBDS\", \"EIF6\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":4,"faith_total":4,"faith_pct":100.0}}