{"gene":"CHP1","run_date":"2026-06-09T22:57:18","timeline":{"discoveries":[{"year":2021,"finding":"CHP1 is an obligate binding partner of NHE1 that promotes NHE1 biosynthetic maturation, cell surface expression, and pH-sensitivity. Cryo-EM structures of the human NHE1-CHP1 complex in inward-facing and inhibitor-bound outward-facing conformations show NHE1 assembles as a symmetrical homodimer undergoing elevator-like conformational changes; CHP1 differentially associates with the two conformational states of each NHE1 monomer, underlying regulation of pH-sensitivity.","method":"Cryo-EM structure determination of NHE1-CHP1 complex in two conformational states","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structures at two conformational states with functional context, revealing molecular mechanism of CHP1-mediated NHE1 regulation","pmids":["34108458"],"is_preprint":false},{"year":2022,"finding":"CHP1 binds NHE3 and facilitates its maturation, plasmalemmal expression, and pH sensitivity. Cryo-EM structure of the human NHE3-CHP1 complex in inward-facing conformation reveals a cytosolic helix-loop-helix autoinhibitory element that blocks the intracellular cavity, and two phosphatidylinositol molecules that bind juxtamembrane sides to stabilize the complex and may enhance transport activity.","method":"Cryo-EM structure determination of NHE3-CHP1 complex","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 1 / Moderate — cryo-EM structure with functional interpretation, single study with rigorous structural data","pmids":["35613257"],"is_preprint":false},{"year":2019,"finding":"CHP1 binds and activates GPAT4, which catalyzes the initial rate-limiting step in glycerolipid synthesis at the ER. CHP1 N-myristoylation is required for this activation, forming a key molecular interface between CHP1 and GPAT4. Loss of CHP1 severely reduces fatty acid incorporation and storage in mammalian cells and invertebrates.","method":"CRISPR-based genetic screens, unbiased lipidomics, binding and activity assays, N-myristoylation mutagenesis","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods (genetic screens, lipidomics, biochemical activity assays, mutagenesis) in a single rigorous study","pmids":["30846317"],"is_preprint":false},{"year":2025,"finding":"CHP1 is a critical regulator of both GPAT3 and GPAT4, required for their stability, enzymatic activity, and lipid droplet localization. CHP1 also facilitates localization of downstream TAG synthesis enzymes AGPAT3 and DGAT2 to lipid droplets by circumventing seipin-mediated restriction. Hydrophobic interfaces mediating CHP1-GPAT interaction were identified by structural modeling and mutational analyses.","method":"Mutational analyses, structural modeling, enzymatic activity assays, lipid droplet imaging, loss-of-function experiments","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — multiple orthogonal methods including mutagenesis, activity assays, and localization studies in a single focused study","pmids":["40875810"],"is_preprint":false},{"year":2013,"finding":"CHP1 assists in the full glycosylation (biosynthetic maturation) of NHE1 required for membrane localization of this transporter. Truncated CHP1 isoforms with mutations in the EF-hand domain are defective in stimulating NHE1 biosynthetic maturation, resulting in reduced membrane localization of NHE1 at axon terminals and subsequent Purkinje cell axon degeneration. Genetic ablation of Nhe1 also causes Purkinje cell axon degeneration, confirming functional convergence.","method":"Positional cloning, point mutagenesis, subcellular fractionation, genetic epistasis (Nhe1 knockout)","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (fractionation, mutagenesis, genetic ablation epistasis) in single rigorous study","pmids":["23904602"],"is_preprint":false},{"year":2018,"finding":"Mutant CHP1 (p.K19del) fails to integrate into functional protein complexes and is prone to aggregation, leading to diminished soluble CHP1 and reduced membrane targeting of NHE1, causing cerebellar ataxia. Wild-type but not mutant human CHP1 mRNA rescued Chp1-deficient zebrafish movement defects and cerebellar hypoplasia.","method":"Subcellular fractionation, size-exclusion chromatography, fluorescence microscopy, zebrafish Morpholino rescue experiments","journal":"Neurology. Genetics","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (fractionation, SEC, fluorescence, in vivo rescue) in single study","pmids":["29379881"],"is_preprint":false},{"year":2018,"finding":"CHP1 directly interacts with PLS3 (Plastin 3), confirmed by co-immunoprecipitation and pull-down assays. CHP1 acts as an inhibitor of calcineurin phosphatase; CHP1 reduction restores calcineurin activity, leading to dephosphorylation of dynamin 1 and restoration of macropinocytosis in Smn-depleted motor neuron cells.","method":"Yeast-two-hybrid screen, co-immunoprecipitation, pull-down assay, macropinocytosis assay, calcineurin phosphatase activity assay, phosphorylation analysis","journal":"Brain","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP confirmed interaction, multiple functional assays including phosphatase activity and downstream substrate phosphorylation","pmids":["29961886"],"is_preprint":false},{"year":2010,"finding":"CHP1 localizes to the plasma membrane, Golgi, and nucleus in a regulated manner: predominantly nuclear in quiescent fibroblasts and translocated to cytoplasmic compartments upon growth stimulation. Nuclear CHP1 binds upstream binding factor (UBF), a component of the RNA polymerase I complex, in a Ca2+-inhibitable manner, and nuclear retention of CHP1 attenuates UBF nucleolar abundance and inhibits rRNA synthesis.","method":"Subcellular fractionation, co-precipitation/pulldown screen, nuclear export motif mutagenesis, rRNA synthesis assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — nuclear localization experiments with mutagenesis plus co-precipitation and functional rRNA assay, single lab","pmids":["20720019"],"is_preprint":false},{"year":2020,"finding":"Ca2+ induces conformational changes in CHP1 (detected by fluorescent probe hydrophobicity assay), but unlike CHP2, the CHP1 hydrophobic pocket that binds the NHE1 CHP-binding domain (CBD) remains accessible in the absence of Ca2+. Both CHP1 and CHP2 interact with CBD with nanomolar affinity (ITC), but Ca2+ depletion does not significantly affect CHP1:CBD affinity (whereas it reduces CHP2:CBD affinity 7-fold), indicating isoform-specific Ca2+-dependent regulation of NHE1 interaction.","method":"Fluorescent probe hydrophobicity (FPH) assay, isothermal titration calorimetry (ITC)","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two orthogonal biochemical methods (FPH and ITC), single lab","pmids":["31912575"],"is_preprint":false},{"year":2025,"finding":"CHP1 serves as a scaffold protein that undergoes phosphorylation by CaMK4, which enhances localization of the Calhm6-CHP1-CaMK4 complex to the cell membrane, promoting Creb1 activation and M2-like macrophage polarization in a calcium-dependent manner.","method":"Co-immunoprecipitation, phosphorylation assay, membrane fractionation, macrophage polarization assays","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2-3 / Weak — co-IP and functional polarization assays, single study, limited mechanistic depth in abstract","pmids":["40999918"],"is_preprint":false},{"year":2026,"finding":"CHP1 interacts with transmembrane protein 87A (TMEM87A), forming a mechanosensing complex. CHP1 ablation disrupts spheroid morphogenesis and the CHP1-TMEM87A complex regulates metastasis via the YAP-GPC6-WNT5A/Hedgehog signaling axis. Disruption of CHP1-TMEM87A binding by sodium gluconate inhibits downstream Hedgehog/PTCH1 signaling.","method":"Co-immunoprecipitation, CETSA, microscale thermophoresis, surface plasmon resonance, in vivo orthotopic tumor model","journal":"Molecular biomedicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal binding assays (CETSA, MST, SPR, Co-IP) plus in vivo validation, single study","pmids":["42258092"],"is_preprint":false},{"year":2026,"finding":"EX-4 (Exendin-4) binds CHP1 directly (identified by proteome microarray and pull-down LC-MS/MS), reducing CHP1 protein expression concentration-dependently. This interaction alleviates apoptosis and restores calcium homeostasis through the CHP1/NHE1 complex. CHP1 knockdown or overexpression reverses the inhibitory effects of EX-4 on apoptosis and calcium signaling.","method":"Proteome microarray, pull-down LC-MS/MS, CHP1 knockdown/overexpression, in vitro and in vivo AMD model","journal":"Biochemical pharmacology","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — direct binding identified by unbiased pull-down MS, confirmed by functional gain/loss-of-function, single study","pmids":["41679663"],"is_preprint":false}],"current_model":"CHP1 (calcineurin B homologous protein 1) is an N-myristoylated EF-hand Ca2+-binding protein that functions as an obligate regulatory subunit of NHE1 and NHE3 sodium/proton exchangers (promoting their glycosylation, biosynthetic maturation, and membrane targeting), a direct activator of GPAT3/4 (rate-limiting enzymes in ER glycerolipid/TAG synthesis), a scaffold/inhibitor of calcineurin phosphatase activity (thereby regulating dynamin-1 phosphorylation and endocytosis), and a nuclear binding partner of UBF that inhibits rRNA synthesis; structurally, cryo-EM has defined how CHP1 differentially contacts the two conformational states of the NHE1 and NHE3 dimers to confer pH sensitivity."},"narrative":{"mechanistic_narrative":"CHP1 (calcineurin B homologous protein 1) is an N-myristoylated EF-hand Ca2+-binding protein that acts as an obligate regulatory subunit and chaperone for membrane transporters and a multifunctional intracellular scaffold [PMID:34108458, PMID:30846317]. Its best-defined role is as an obligate binding partner of the sodium/proton exchangers NHE1 and NHE3, where it promotes biosynthetic maturation (glycosylation), cell-surface expression, and pH-sensitivity; cryo-EM of both complexes shows CHP1 differentially engaging the inward- and outward-facing elevator states of the transporter dimer to confer pH regulation [PMID:34108458, PMID:35613257]. Loss of correct CHP1-dependent NHE1 maturation underlies disease: truncating EF-hand mutants and the aggregation-prone p.K19del allele reduce soluble CHP1 and NHE1 membrane targeting, causing cerebellar ataxia and Purkinje cell axon degeneration, with wild-type human CHP1 rescuing Chp1-deficient zebrafish phenotypes [PMID:23904602, PMID:29379881]. In parallel, CHP1 binds and activates the rate-limiting ER glycerolipid-synthesis enzymes GPAT4 and GPAT3, an interaction dependent on CHP1 N-myristoylation and required for GPAT stability, activity, and lipid-droplet localization, thereby controlling fatty acid incorporation and triacylglycerol storage [PMID:30846317, PMID:40875810]. Beyond transport and lipid metabolism, CHP1 functions as a calcium-dependent scaffold and calcineurin inhibitor: it interacts with PLS3 and restrains calcineurin to control dynamin-1 dephosphorylation and macropinocytosis [PMID:29961886], and nuclear CHP1 binds the RNA polymerase I factor UBF in a Ca2+-inhibitable manner to attenuate rRNA synthesis [PMID:20720019].","teleology":[{"year":2010,"claim":"Established that CHP1 is not solely a membrane-associated cofactor but shuttles between plasma membrane, Golgi, and nucleus, linking its localization to a transcriptional function previously unrecognized for this Ca2+-binding protein.","evidence":"Subcellular fractionation, co-precipitation screen, nuclear export motif mutagenesis, and rRNA synthesis assay in fibroblasts","pmids":["20720019"],"confidence":"Medium","gaps":["Mechanism of Ca2+-regulated nucleocytoplasmic shuttling not structurally defined","Direct effect on Pol I transcription machinery beyond UBF abundance not resolved"]},{"year":2013,"claim":"Resolved how CHP1 functionally supports NHE1, showing it is required for full glycosylation/maturation and membrane delivery, and that EF-hand mutants phenocopy Nhe1 loss in causing Purkinje axon degeneration.","evidence":"Positional cloning, point mutagenesis, subcellular fractionation, and Nhe1-knockout genetic epistasis in mouse","pmids":["23904602"],"confidence":"High","gaps":["Molecular basis of glycosylation defect not defined","Whether NHE1 alone accounts for the neurodegenerative phenotype unresolved"]},{"year":2018,"claim":"Defined a CHP1-calcineurin signaling axis, showing CHP1 inhibits calcineurin and interacts with PLS3, and that lowering CHP1 restores dynamin-1 dephosphorylation and macropinocytosis in SMN-depleted motor neurons.","evidence":"Yeast two-hybrid, reciprocal co-IP, pull-down, calcineurin phosphatase activity, phosphorylation, and macropinocytosis assays","pmids":["29961886"],"confidence":"High","gaps":["Stoichiometry of CHP1-calcineurin inhibition not quantified","Functional role of PLS3 interaction not fully separated from calcineurin effect"]},{"year":2018,"claim":"Connected CHP1 to human disease, demonstrating the p.K19del mutant aggregates and fails to assemble into functional complexes, reducing NHE1 membrane targeting and causing cerebellar ataxia.","evidence":"Subcellular fractionation, size-exclusion chromatography, fluorescence microscopy, and zebrafish morpholino rescue with human CHP1 mRNA","pmids":["29379881"],"confidence":"High","gaps":["How aggregation is triggered at the structural level unresolved","Contribution of non-NHE1 CHP1 functions to ataxia not assessed"]},{"year":2019,"claim":"Identified a metabolic function distinct from transport regulation, showing CHP1 binds and activates GPAT4 via an N-myristoylation-dependent interface to drive ER glycerolipid synthesis and lipid storage.","evidence":"CRISPR screens, lipidomics, binding/activity assays, and N-myristoylation mutagenesis in mammalian cells and invertebrates","pmids":["30846317"],"confidence":"High","gaps":["Whether CHP1 Ca2+-binding modulates GPAT activation not tested","Structural basis of the GPAT4 interface not determined at this stage"]},{"year":2020,"claim":"Clarified the Ca2+-dependence of CHP1-NHE1 binding, showing CHP1 retains an accessible hydrophobic CBD-binding pocket even without Ca2+, distinguishing its regulation from the Ca2+-sensitive paralog CHP2.","evidence":"Fluorescent probe hydrophobicity assay and isothermal titration calorimetry on CHP1/CHP2 with the NHE1 CHP-binding domain","pmids":["31912575"],"confidence":"Medium","gaps":["Physiological consequence of Ca2+-independent CBD binding in cells not shown","Does not address Ca2+ effects on full-length transporter regulation"]},{"year":2021,"claim":"Provided the structural mechanism of CHP1-mediated NHE1 regulation, showing NHE1 is a symmetrical dimer using elevator motions and that CHP1 differentially contacts the two conformational states to confer pH-sensitivity.","evidence":"Cryo-EM of human NHE1-CHP1 in inward-facing and inhibitor-bound outward-facing conformations","pmids":["34108458"],"confidence":"High","gaps":["Dynamics of the conformational cycle in a membrane not directly observed","Role of CHP1 myristoylation in the structural context not resolved"]},{"year":2022,"claim":"Extended the structural model to NHE3, revealing an autoinhibitory helix-loop-helix element blocking the cavity and two phosphatidylinositol lipids stabilizing the CHP1-bound complex.","evidence":"Cryo-EM of the human NHE3-CHP1 complex in inward-facing conformation","pmids":["35613257"],"confidence":"High","gaps":["Outward-facing NHE3-CHP1 state not captured","Functional role of bound phosphatidylinositol on transport rate not directly demonstrated"]},{"year":2025,"claim":"Broadened the lipid-synthesis role, showing CHP1 is required for both GPAT3 and GPAT4 stability, activity, and lipid-droplet targeting and helps route AGPAT3 and DGAT2 to droplets past seipin-mediated restriction.","evidence":"Mutational analyses, structural modeling, enzymatic activity assays, lipid-droplet imaging, and loss-of-function experiments","pmids":["40875810"],"confidence":"High","gaps":["Direct structures of CHP1-GPAT complexes not solved","Mechanism of bypassing seipin restriction not defined"]},{"year":2025,"claim":"Implicated CHP1 as a phosphorylated scaffold in immune signaling, where CaMK4 phosphorylation drives Calhm6-CHP1-CaMK4 membrane localization to promote CREB1 activation and M2 macrophage polarization.","evidence":"Co-IP, phosphorylation assay, membrane fractionation, and macrophage polarization assays","pmids":["40999918"],"confidence":"Medium","gaps":["CaMK4 phosphosite on CHP1 not mapped","Direct vs indirect role of CHP1 in CREB1 activation not separated"]},{"year":2026,"claim":"Linked CHP1 to mechanosensing and tumor biology through a CHP1-TMEM87A complex regulating YAP-GPC6-WNT5A/Hedgehog signaling and metastasis.","evidence":"Co-IP, CETSA, microscale thermophoresis, surface plasmon resonance, and in vivo orthotopic tumor model","pmids":["42258092"],"confidence":"Medium","gaps":["Structural basis of CHP1-TMEM87A binding not resolved","How CHP1 transduces mechanical input to the signaling axis unclear"]},{"year":2026,"claim":"Identified CHP1 as a direct drug target, where Exendin-4 binding reduces CHP1 levels and modulates apoptosis and calcium homeostasis via the CHP1/NHE1 complex.","evidence":"Proteome microarray, pull-down LC-MS/MS, CHP1 knockdown/overexpression in in vitro and in vivo AMD models","pmids":["41679663"],"confidence":"Medium","gaps":["Binding site of Exendin-4 on CHP1 not mapped","Mechanism by which binding lowers CHP1 protein levels not defined"]},{"year":null,"claim":"How CHP1's distinct activities — transporter chaperoning, GPAT activation, calcineurin inhibition, and nuclear UBF binding — are coordinated by Ca2+ and myristoylation within a single cell remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model integrating Ca2+ sensing across CHP1's multiple effector complexes","Whether competing partners share the same hydrophobic pocket is undefined","Tissue-specific dominance of each function not established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,1,2,3,6]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[6,9,10]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1,4,7,9]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[2,3]},{"term_id":"GO:0005811","term_label":"lipid droplet","supporting_discovery_ids":[3]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[7]},{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[7]},{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[7]}],"pathway":[{"term_id":"R-HSA-382551","term_label":"Transport of small molecules","supporting_discovery_ids":[0,1,4]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[2,3]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[6,9,10]}],"complexes":["NHE1-CHP1 complex","NHE3-CHP1 complex","Calhm6-CHP1-CaMK4 complex"],"partners":["NHE1","NHE3","GPAT4","GPAT3","PLS3","UBF","TMEM87A","CAMK4"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q99653","full_name":"Calcineurin B homologous protein 1","aliases":["Calcineurin B-like protein","Calcium-binding protein CHP","Calcium-binding protein p22","EF-hand calcium-binding domain-containing protein p22"],"length_aa":195,"mass_kda":22.5,"function":"Calcium-binding protein involved in different processes such as regulation of vesicular trafficking, plasma membrane Na(+)/H(+) exchanger and gene transcription. Involved in the constitutive exocytic membrane traffic. Mediates the association between microtubules and membrane-bound organelles of the endoplasmic reticulum and Golgi apparatus and is also required for the targeting and fusion of transcytotic vesicles (TCV) with the plasma membrane. Functions as an integral cofactor in cell pH regulation by controlling plasma membrane-type Na(+)/H(+) exchange activity. Affects the pH sensitivity of SLC9A1/NHE1 by increasing its sensitivity at acidic pH. Required for the stabilization and localization of SLC9A1/NHE1 at the plasma membrane. Inhibits serum- and GTPase-stimulated Na(+)/H(+) exchange. Plays a role as an inhibitor of ribosomal RNA transcription by repressing the nucleolar UBF1 transcriptional activity. May sequester UBF1 in the nucleoplasm and limit its translocation to the nucleolus. Associates to the ribosomal gene promoter. Acts as a negative regulator of the calcineurin/NFAT signaling pathway. Inhibits NFAT nuclear translocation and transcriptional activity by suppressing the calcium-dependent calcineurin phosphatase activity. Also negatively regulates the kinase activity of the apoptosis-induced kinase STK17B. Inhibits both STK17B auto- and substrate-phosphorylations in a calcium-dependent manner","subcellular_location":"Nucleus; Cytoplasm; Cytoplasm, cytoskeleton; Endomembrane system; Endoplasmic reticulum-Golgi intermediate compartment; Endoplasmic reticulum; Cell membrane; Membrane","url":"https://www.uniprot.org/uniprotkb/Q99653/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CHP1","classification":"Not Classified","n_dependent_lines":94,"n_total_lines":1208,"dependency_fraction":0.07781456953642384},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"GPAT3","stoichiometry":10.0},{"gene":"GPAT4","stoichiometry":10.0}],"url":"https://opencell.sf.czbiohub.org/search/CHP1","total_profiled":1310},"omim":[{"mim_id":"618438","title":"SPASTIC ATAXIA 9, AUTOSOMAL RECESSIVE; SPAX9","url":"https://www.omim.org/entry/618438"},{"mim_id":"606988","title":"CALCINEURIN-LIKE EF-HAND PROTEIN 1; CHP1","url":"https://www.omim.org/entry/606988"},{"mim_id":"604353","title":"CYSTEINE- AND HISTIDINE-RICH DOMAIN-CONTAINING PROTEIN 1; CHORDC1","url":"https://www.omim.org/entry/604353"},{"mim_id":"117139","title":"CENTROMERIC PROTEIN A; CENPA","url":"https://www.omim.org/entry/117139"},{"mim_id":"108600","title":"SPASTIC ATAXIA 1, AUTOSOMAL DOMINANT; SPAX1","url":"https://www.omim.org/entry/108600"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/CHP1"},"hgnc":{"alias_symbol":["Sid470p","CHP","SLC9A1BP","p22","p24"],"prev_symbol":[]},"alphafold":{"accession":"Q99653","domains":[{"cath_id":"1.10.238.10","chopping":"10-89","consensus_level":"medium","plddt":92.4852,"start":10,"end":89},{"cath_id":"1.10.238.10","chopping":"108-188","consensus_level":"medium","plddt":93.5001,"start":108,"end":188}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q99653","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q99653-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q99653-F1-predicted_aligned_error_v6.png","plddt_mean":89.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CHP1","jax_strain_url":"https://www.jax.org/strain/search?query=CHP1"},"sequence":{"accession":"Q99653","fasta_url":"https://rest.uniprot.org/uniprotkb/Q99653.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q99653/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q99653"}},"corpus_meta":[{"pmid":"15372076","id":"PMC_15372076","title":"A chromodomain protein, Chp1, is required for the establishment of heterochromatin in fission yeast.","date":"2004","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/15372076","citation_count":179,"is_preprint":false},{"pmid":"30846317","id":"PMC_30846317","title":"CHP1 Regulates Compartmentalized Glycerolipid Synthesis by Activating GPAT4.","date":"2019","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/30846317","citation_count":85,"is_preprint":false},{"pmid":"34108458","id":"PMC_34108458","title":"Structure and mechanism of the human NHE1-CHP1 complex.","date":"2021","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/34108458","citation_count":74,"is_preprint":false},{"pmid":"15743828","id":"PMC_15743828","title":"RNA interference (RNAi)-dependent and RNAi-independent association of the Chp1 chromodomain protein with distinct heterochromatic loci in fission yeast.","date":"2005","source":"Molecular and cellular 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interacts with upstream binding factor and inhibits ribosomal RNA synthesis.","date":"2010","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/20720019","citation_count":12,"is_preprint":false},{"pmid":"32002604","id":"PMC_32002604","title":"Azorhizobium caulinodans c-di-GMP phosphodiesterase Chp1 involved in motility, EPS production, and nodulation of the host plant.","date":"2020","source":"Applied microbiology and biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/32002604","citation_count":11,"is_preprint":false},{"pmid":"26762899","id":"PMC_26762899","title":"The canine prostate cancer cell line CHP-1 shows over-expression of the co-chaperone small glutamine-rich tetratricopeptide repeat-containing protein α.","date":"2016","source":"Veterinary and comparative oncology","url":"https://pubmed.ncbi.nlm.nih.gov/26762899","citation_count":10,"is_preprint":false},{"pmid":"31917826","id":"PMC_31917826","title":"The C. elegans CHP1 homolog, pbo-1, functions in innate immunity by regulating the pH of the intestinal lumen.","date":"2020","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/31917826","citation_count":9,"is_preprint":false},{"pmid":"35724821","id":"PMC_35724821","title":"Combinatorial ASO-mediated therapy with low dose SMN and the protective modifier Chp1 is not sufficient to ameliorate SMA pathology hallmarks.","date":"2022","source":"Neurobiology of disease","url":"https://pubmed.ncbi.nlm.nih.gov/35724821","citation_count":7,"is_preprint":false},{"pmid":"31607845","id":"PMC_31607845","title":"PLS3 Overexpression Delays Ataxia in Chp1 Mutant Mice.","date":"2019","source":"Frontiers in neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/31607845","citation_count":6,"is_preprint":false},{"pmid":"31912575","id":"PMC_31912575","title":"Calcium affects CHP1 and CHP2 conformation and their interaction with sodium/proton exchanger 1.","date":"2020","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/31912575","citation_count":5,"is_preprint":false},{"pmid":"32053105","id":"PMC_32053105","title":"The CHORD protein CHP-1 regulates EGF receptor trafficking and signaling in C. elegans and in human cells.","date":"2020","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/32053105","citation_count":5,"is_preprint":false},{"pmid":"40999918","id":"PMC_40999918","title":"Calhm6 Governs Macrophage Polarization Through Chp1-Camk4-Creb1 Axis and Ectosomal Delivery in Inflammatory Responses.","date":"2025","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/40999918","citation_count":4,"is_preprint":false},{"pmid":"31255284","id":"PMC_31255284","title":"Nuclear aconitase antagonizes heterochromatic silencing by interfering with Chp1 binding to DNA.","date":"2019","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/31255284","citation_count":4,"is_preprint":false},{"pmid":"40875810","id":"PMC_40875810","title":"CHP1 promotes lipid droplet growth and regulates the localization of key enzymes for triacylglycerol synthesis.","date":"2025","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/40875810","citation_count":2,"is_preprint":false},{"pmid":"40723891","id":"PMC_40723891","title":"Targeting Sodium Transport Reveals CHP1 Downregulation as a Novel Molecular Feature of Malignant Progression in Clear Cell Renal Cell Carcinoma: Insights from Integrated Multi-Omics Analyses.","date":"2025","source":"Biomolecules","url":"https://pubmed.ncbi.nlm.nih.gov/40723891","citation_count":1,"is_preprint":false},{"pmid":"42258092","id":"PMC_42258092","title":"Targeting the Calcineurin Homologous Protein 1 (CHP1)-Transmembrane Protein 87A (TMEM87A) mechanosensing complex: a druggable vulnerability in metastatic ovarian cancer.","date":"2026","source":"Molecular biomedicine","url":"https://pubmed.ncbi.nlm.nih.gov/42258092","citation_count":0,"is_preprint":false},{"pmid":"41679663","id":"PMC_41679663","title":"Exendin-4 alleviates Aβ1-40-induced apoptosis and calcium dysregulation in RPE cells through the CHP1/NHE1 complex.","date":"2026","source":"Biochemical pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/41679663","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":17454,"output_tokens":3241,"usd":0.050488,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10752,"output_tokens":4496,"usd":0.08308,"stage2_stop_reason":"end_turn"},"total_usd":0.133568,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2021,\n      \"finding\": \"CHP1 is an obligate binding partner of NHE1 that promotes NHE1 biosynthetic maturation, cell surface expression, and pH-sensitivity. Cryo-EM structures of the human NHE1-CHP1 complex in inward-facing and inhibitor-bound outward-facing conformations show NHE1 assembles as a symmetrical homodimer undergoing elevator-like conformational changes; CHP1 differentially associates with the two conformational states of each NHE1 monomer, underlying regulation of pH-sensitivity.\",\n      \"method\": \"Cryo-EM structure determination of NHE1-CHP1 complex in two conformational states\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structures at two conformational states with functional context, revealing molecular mechanism of CHP1-mediated NHE1 regulation\",\n      \"pmids\": [\"34108458\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CHP1 binds NHE3 and facilitates its maturation, plasmalemmal expression, and pH sensitivity. Cryo-EM structure of the human NHE3-CHP1 complex in inward-facing conformation reveals a cytosolic helix-loop-helix autoinhibitory element that blocks the intracellular cavity, and two phosphatidylinositol molecules that bind juxtamembrane sides to stabilize the complex and may enhance transport activity.\",\n      \"method\": \"Cryo-EM structure determination of NHE3-CHP1 complex\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — cryo-EM structure with functional interpretation, single study with rigorous structural data\",\n      \"pmids\": [\"35613257\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CHP1 binds and activates GPAT4, which catalyzes the initial rate-limiting step in glycerolipid synthesis at the ER. CHP1 N-myristoylation is required for this activation, forming a key molecular interface between CHP1 and GPAT4. Loss of CHP1 severely reduces fatty acid incorporation and storage in mammalian cells and invertebrates.\",\n      \"method\": \"CRISPR-based genetic screens, unbiased lipidomics, binding and activity assays, N-myristoylation mutagenesis\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods (genetic screens, lipidomics, biochemical activity assays, mutagenesis) in a single rigorous study\",\n      \"pmids\": [\"30846317\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CHP1 is a critical regulator of both GPAT3 and GPAT4, required for their stability, enzymatic activity, and lipid droplet localization. CHP1 also facilitates localization of downstream TAG synthesis enzymes AGPAT3 and DGAT2 to lipid droplets by circumventing seipin-mediated restriction. Hydrophobic interfaces mediating CHP1-GPAT interaction were identified by structural modeling and mutational analyses.\",\n      \"method\": \"Mutational analyses, structural modeling, enzymatic activity assays, lipid droplet imaging, loss-of-function experiments\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — multiple orthogonal methods including mutagenesis, activity assays, and localization studies in a single focused study\",\n      \"pmids\": [\"40875810\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CHP1 assists in the full glycosylation (biosynthetic maturation) of NHE1 required for membrane localization of this transporter. Truncated CHP1 isoforms with mutations in the EF-hand domain are defective in stimulating NHE1 biosynthetic maturation, resulting in reduced membrane localization of NHE1 at axon terminals and subsequent Purkinje cell axon degeneration. Genetic ablation of Nhe1 also causes Purkinje cell axon degeneration, confirming functional convergence.\",\n      \"method\": \"Positional cloning, point mutagenesis, subcellular fractionation, genetic epistasis (Nhe1 knockout)\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (fractionation, mutagenesis, genetic ablation epistasis) in single rigorous study\",\n      \"pmids\": [\"23904602\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Mutant CHP1 (p.K19del) fails to integrate into functional protein complexes and is prone to aggregation, leading to diminished soluble CHP1 and reduced membrane targeting of NHE1, causing cerebellar ataxia. Wild-type but not mutant human CHP1 mRNA rescued Chp1-deficient zebrafish movement defects and cerebellar hypoplasia.\",\n      \"method\": \"Subcellular fractionation, size-exclusion chromatography, fluorescence microscopy, zebrafish Morpholino rescue experiments\",\n      \"journal\": \"Neurology. Genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (fractionation, SEC, fluorescence, in vivo rescue) in single study\",\n      \"pmids\": [\"29379881\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CHP1 directly interacts with PLS3 (Plastin 3), confirmed by co-immunoprecipitation and pull-down assays. CHP1 acts as an inhibitor of calcineurin phosphatase; CHP1 reduction restores calcineurin activity, leading to dephosphorylation of dynamin 1 and restoration of macropinocytosis in Smn-depleted motor neuron cells.\",\n      \"method\": \"Yeast-two-hybrid screen, co-immunoprecipitation, pull-down assay, macropinocytosis assay, calcineurin phosphatase activity assay, phosphorylation analysis\",\n      \"journal\": \"Brain\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP confirmed interaction, multiple functional assays including phosphatase activity and downstream substrate phosphorylation\",\n      \"pmids\": [\"29961886\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"CHP1 localizes to the plasma membrane, Golgi, and nucleus in a regulated manner: predominantly nuclear in quiescent fibroblasts and translocated to cytoplasmic compartments upon growth stimulation. Nuclear CHP1 binds upstream binding factor (UBF), a component of the RNA polymerase I complex, in a Ca2+-inhibitable manner, and nuclear retention of CHP1 attenuates UBF nucleolar abundance and inhibits rRNA synthesis.\",\n      \"method\": \"Subcellular fractionation, co-precipitation/pulldown screen, nuclear export motif mutagenesis, rRNA synthesis assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — nuclear localization experiments with mutagenesis plus co-precipitation and functional rRNA assay, single lab\",\n      \"pmids\": [\"20720019\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Ca2+ induces conformational changes in CHP1 (detected by fluorescent probe hydrophobicity assay), but unlike CHP2, the CHP1 hydrophobic pocket that binds the NHE1 CHP-binding domain (CBD) remains accessible in the absence of Ca2+. Both CHP1 and CHP2 interact with CBD with nanomolar affinity (ITC), but Ca2+ depletion does not significantly affect CHP1:CBD affinity (whereas it reduces CHP2:CBD affinity 7-fold), indicating isoform-specific Ca2+-dependent regulation of NHE1 interaction.\",\n      \"method\": \"Fluorescent probe hydrophobicity (FPH) assay, isothermal titration calorimetry (ITC)\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two orthogonal biochemical methods (FPH and ITC), single lab\",\n      \"pmids\": [\"31912575\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CHP1 serves as a scaffold protein that undergoes phosphorylation by CaMK4, which enhances localization of the Calhm6-CHP1-CaMK4 complex to the cell membrane, promoting Creb1 activation and M2-like macrophage polarization in a calcium-dependent manner.\",\n      \"method\": \"Co-immunoprecipitation, phosphorylation assay, membrane fractionation, macrophage polarization assays\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Weak — co-IP and functional polarization assays, single study, limited mechanistic depth in abstract\",\n      \"pmids\": [\"40999918\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"CHP1 interacts with transmembrane protein 87A (TMEM87A), forming a mechanosensing complex. CHP1 ablation disrupts spheroid morphogenesis and the CHP1-TMEM87A complex regulates metastasis via the YAP-GPC6-WNT5A/Hedgehog signaling axis. Disruption of CHP1-TMEM87A binding by sodium gluconate inhibits downstream Hedgehog/PTCH1 signaling.\",\n      \"method\": \"Co-immunoprecipitation, CETSA, microscale thermophoresis, surface plasmon resonance, in vivo orthotopic tumor model\",\n      \"journal\": \"Molecular biomedicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal binding assays (CETSA, MST, SPR, Co-IP) plus in vivo validation, single study\",\n      \"pmids\": [\"42258092\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"EX-4 (Exendin-4) binds CHP1 directly (identified by proteome microarray and pull-down LC-MS/MS), reducing CHP1 protein expression concentration-dependently. This interaction alleviates apoptosis and restores calcium homeostasis through the CHP1/NHE1 complex. CHP1 knockdown or overexpression reverses the inhibitory effects of EX-4 on apoptosis and calcium signaling.\",\n      \"method\": \"Proteome microarray, pull-down LC-MS/MS, CHP1 knockdown/overexpression, in vitro and in vivo AMD model\",\n      \"journal\": \"Biochemical pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — direct binding identified by unbiased pull-down MS, confirmed by functional gain/loss-of-function, single study\",\n      \"pmids\": [\"41679663\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CHP1 (calcineurin B homologous protein 1) is an N-myristoylated EF-hand Ca2+-binding protein that functions as an obligate regulatory subunit of NHE1 and NHE3 sodium/proton exchangers (promoting their glycosylation, biosynthetic maturation, and membrane targeting), a direct activator of GPAT3/4 (rate-limiting enzymes in ER glycerolipid/TAG synthesis), a scaffold/inhibitor of calcineurin phosphatase activity (thereby regulating dynamin-1 phosphorylation and endocytosis), and a nuclear binding partner of UBF that inhibits rRNA synthesis; structurally, cryo-EM has defined how CHP1 differentially contacts the two conformational states of the NHE1 and NHE3 dimers to confer pH sensitivity.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CHP1 (calcineurin B homologous protein 1) is an N-myristoylated EF-hand Ca2+-binding protein that acts as an obligate regulatory subunit and chaperone for membrane transporters and a multifunctional intracellular scaffold [#0, #2]. Its best-defined role is as an obligate binding partner of the sodium/proton exchangers NHE1 and NHE3, where it promotes biosynthetic maturation (glycosylation), cell-surface expression, and pH-sensitivity; cryo-EM of both complexes shows CHP1 differentially engaging the inward- and outward-facing elevator states of the transporter dimer to confer pH regulation [#0, #1]. Loss of correct CHP1-dependent NHE1 maturation underlies disease: truncating EF-hand mutants and the aggregation-prone p.K19del allele reduce soluble CHP1 and NHE1 membrane targeting, causing cerebellar ataxia and Purkinje cell axon degeneration, with wild-type human CHP1 rescuing Chp1-deficient zebrafish phenotypes [#4, #5]. In parallel, CHP1 binds and activates the rate-limiting ER glycerolipid-synthesis enzymes GPAT4 and GPAT3, an interaction dependent on CHP1 N-myristoylation and required for GPAT stability, activity, and lipid-droplet localization, thereby controlling fatty acid incorporation and triacylglycerol storage [#2, #3]. Beyond transport and lipid metabolism, CHP1 functions as a calcium-dependent scaffold and calcineurin inhibitor: it interacts with PLS3 and restrains calcineurin to control dynamin-1 dephosphorylation and macropinocytosis [#6], and nuclear CHP1 binds the RNA polymerase I factor UBF in a Ca2+-inhibitable manner to attenuate rRNA synthesis [#7].\",\n  \"teleology\": [\n    {\n      \"year\": 2010,\n      \"claim\": \"Established that CHP1 is not solely a membrane-associated cofactor but shuttles between plasma membrane, Golgi, and nucleus, linking its localization to a transcriptional function previously unrecognized for this Ca2+-binding protein.\",\n      \"evidence\": \"Subcellular fractionation, co-precipitation screen, nuclear export motif mutagenesis, and rRNA synthesis assay in fibroblasts\",\n      \"pmids\": [\"20720019\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of Ca2+-regulated nucleocytoplasmic shuttling not structurally defined\", \"Direct effect on Pol I transcription machinery beyond UBF abundance not resolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Resolved how CHP1 functionally supports NHE1, showing it is required for full glycosylation/maturation and membrane delivery, and that EF-hand mutants phenocopy Nhe1 loss in causing Purkinje axon degeneration.\",\n      \"evidence\": \"Positional cloning, point mutagenesis, subcellular fractionation, and Nhe1-knockout genetic epistasis in mouse\",\n      \"pmids\": [\"23904602\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of glycosylation defect not defined\", \"Whether NHE1 alone accounts for the neurodegenerative phenotype unresolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defined a CHP1-calcineurin signaling axis, showing CHP1 inhibits calcineurin and interacts with PLS3, and that lowering CHP1 restores dynamin-1 dephosphorylation and macropinocytosis in SMN-depleted motor neurons.\",\n      \"evidence\": \"Yeast two-hybrid, reciprocal co-IP, pull-down, calcineurin phosphatase activity, phosphorylation, and macropinocytosis assays\",\n      \"pmids\": [\"29961886\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry of CHP1-calcineurin inhibition not quantified\", \"Functional role of PLS3 interaction not fully separated from calcineurin effect\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Connected CHP1 to human disease, demonstrating the p.K19del mutant aggregates and fails to assemble into functional complexes, reducing NHE1 membrane targeting and causing cerebellar ataxia.\",\n      \"evidence\": \"Subcellular fractionation, size-exclusion chromatography, fluorescence microscopy, and zebrafish morpholino rescue with human CHP1 mRNA\",\n      \"pmids\": [\"29379881\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How aggregation is triggered at the structural level unresolved\", \"Contribution of non-NHE1 CHP1 functions to ataxia not assessed\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified a metabolic function distinct from transport regulation, showing CHP1 binds and activates GPAT4 via an N-myristoylation-dependent interface to drive ER glycerolipid synthesis and lipid storage.\",\n      \"evidence\": \"CRISPR screens, lipidomics, binding/activity assays, and N-myristoylation mutagenesis in mammalian cells and invertebrates\",\n      \"pmids\": [\"30846317\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether CHP1 Ca2+-binding modulates GPAT activation not tested\", \"Structural basis of the GPAT4 interface not determined at this stage\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Clarified the Ca2+-dependence of CHP1-NHE1 binding, showing CHP1 retains an accessible hydrophobic CBD-binding pocket even without Ca2+, distinguishing its regulation from the Ca2+-sensitive paralog CHP2.\",\n      \"evidence\": \"Fluorescent probe hydrophobicity assay and isothermal titration calorimetry on CHP1/CHP2 with the NHE1 CHP-binding domain\",\n      \"pmids\": [\"31912575\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological consequence of Ca2+-independent CBD binding in cells not shown\", \"Does not address Ca2+ effects on full-length transporter regulation\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Provided the structural mechanism of CHP1-mediated NHE1 regulation, showing NHE1 is a symmetrical dimer using elevator motions and that CHP1 differentially contacts the two conformational states to confer pH-sensitivity.\",\n      \"evidence\": \"Cryo-EM of human NHE1-CHP1 in inward-facing and inhibitor-bound outward-facing conformations\",\n      \"pmids\": [\"34108458\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Dynamics of the conformational cycle in a membrane not directly observed\", \"Role of CHP1 myristoylation in the structural context not resolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Extended the structural model to NHE3, revealing an autoinhibitory helix-loop-helix element blocking the cavity and two phosphatidylinositol lipids stabilizing the CHP1-bound complex.\",\n      \"evidence\": \"Cryo-EM of the human NHE3-CHP1 complex in inward-facing conformation\",\n      \"pmids\": [\"35613257\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Outward-facing NHE3-CHP1 state not captured\", \"Functional role of bound phosphatidylinositol on transport rate not directly demonstrated\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Broadened the lipid-synthesis role, showing CHP1 is required for both GPAT3 and GPAT4 stability, activity, and lipid-droplet targeting and helps route AGPAT3 and DGAT2 to droplets past seipin-mediated restriction.\",\n      \"evidence\": \"Mutational analyses, structural modeling, enzymatic activity assays, lipid-droplet imaging, and loss-of-function experiments\",\n      \"pmids\": [\"40875810\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct structures of CHP1-GPAT complexes not solved\", \"Mechanism of bypassing seipin restriction not defined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Implicated CHP1 as a phosphorylated scaffold in immune signaling, where CaMK4 phosphorylation drives Calhm6-CHP1-CaMK4 membrane localization to promote CREB1 activation and M2 macrophage polarization.\",\n      \"evidence\": \"Co-IP, phosphorylation assay, membrane fractionation, and macrophage polarization assays\",\n      \"pmids\": [\"40999918\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"CaMK4 phosphosite on CHP1 not mapped\", \"Direct vs indirect role of CHP1 in CREB1 activation not separated\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Linked CHP1 to mechanosensing and tumor biology through a CHP1-TMEM87A complex regulating YAP-GPC6-WNT5A/Hedgehog signaling and metastasis.\",\n      \"evidence\": \"Co-IP, CETSA, microscale thermophoresis, surface plasmon resonance, and in vivo orthotopic tumor model\",\n      \"pmids\": [\"42258092\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of CHP1-TMEM87A binding not resolved\", \"How CHP1 transduces mechanical input to the signaling axis unclear\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Identified CHP1 as a direct drug target, where Exendin-4 binding reduces CHP1 levels and modulates apoptosis and calcium homeostasis via the CHP1/NHE1 complex.\",\n      \"evidence\": \"Proteome microarray, pull-down LC-MS/MS, CHP1 knockdown/overexpression in in vitro and in vivo AMD models\",\n      \"pmids\": [\"41679663\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Binding site of Exendin-4 on CHP1 not mapped\", \"Mechanism by which binding lowers CHP1 protein levels not defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How CHP1's distinct activities — transporter chaperoning, GPAT activation, calcineurin inhibition, and nuclear UBF binding — are coordinated by Ca2+ and myristoylation within a single cell remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model integrating Ca2+ sensing across CHP1's multiple effector complexes\", \"Whether competing partners share the same hydrophobic pocket is undefined\", \"Tissue-specific dominance of each function not established\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1, 2, 3, 6]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [6, 9, 10]},\n      {\"term_id\": \"GO:0005509\", \"supporting_discovery_ids\": [7, 8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1, 4, 7, 9]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [2, 3]},\n      {\"term_id\": \"GO:0005811\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-382551\", \"supporting_discovery_ids\": [0, 1, 4]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [2, 3]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [6, 9, 10]}\n    ],\n    \"complexes\": [\n      \"NHE1-CHP1 complex\",\n      \"NHE3-CHP1 complex\",\n      \"Calhm6-CHP1-CaMK4 complex\"\n    ],\n    \"partners\": [\n      \"NHE1\",\n      \"NHE3\",\n      \"GPAT4\",\n      \"GPAT3\",\n      \"PLS3\",\n      \"UBF\",\n      \"TMEM87A\",\n      \"CaMK4\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}