{"gene":"CABP1","run_date":"2026-06-09T22:57:17","timeline":{"discoveries":[{"year":2005,"finding":"CaBP1 binds Mg2+ constitutively at EF-1 (Kd ~300 µM) and binds Ca2+ cooperatively at EF-3 and EF-4 (Kd ~2.5 µM); no Ca2+ binding detected at EF-2. Mg2+ and Ca2+ induce distinct conformational changes that promote protein dimerization and increased folding stability, suggesting CaBP1 switches between structurally distinct Mg2+-bound and Ca2+-bound states in response to Ca2+ signaling.","method":"NMR spectroscopy, isothermal titration calorimetry (ITC), and other biophysical analyses of recombinant CaBP1","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal biophysical methods (NMR, ITC, thermal stability) in a single rigorous study, with site-specific resolution of each EF-hand","pmids":["16147998"],"is_preprint":false},{"year":2008,"finding":"NMR structures of CaBP1 in Mg2+-bound and Ca2+-bound states show the N-domain (EF1/EF2) adopts a closed conformation with Mg2+ at EF1, while the C-domain undergoes a Ca2+-induced closed-to-open transition (like calmodulin), exposing hydrophobic residues (Leu132, His134, Ile141, Ile144, Val148). Ca2+-bound CaBP1 C-domain binds the N-terminal suppressor and ligand-binding core domains of InsP3R1 (residues 1–587) via ITC, whereas the CaBP1 N-domain and calmodulin did not show appreciable binding under these conditions.","method":"NMR structure determination, isothermal titration calorimetry","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — NMR structures of two states plus ITC binding measurements, multiple orthogonal methods in one study","pmids":["19008222"],"is_preprint":false},{"year":2013,"finding":"CaBP1 inhibits InsP3R activity by clamping intersubunit interactions: the CaBP1 C-lobe binds the β-domain of the InsP3-binding core of InsP3R1 via a hydrophobic cluster (V101, L104, V162 on CaBP1; L302, I364, L393 on InsP3R). CaBP1 promotes the intersubunit interface between the suppressor domain and the InsP3-binding core β-domain, the same interface that InsP3 disrupts to initiate gating. Thus CaBP1 slows InsP3R opening by restricting the conformational changes required for gating, and this inhibition is enhanced by Ca2+ binding to both CaBP1 and InsP3R.","method":"NMR paramagnetic relaxation enhancement, targeted cross-linking, Ca2+ flux assays, mutagenesis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — NMR PRE structural restraints, mutagenesis of key interface residues, cross-linking functional assay, and Ca2+ flux measurements; multiple orthogonal methods","pmids":["23650371"],"is_preprint":false},{"year":2010,"finding":"CaBP1 inhibits CaV1.2 calcium-dependent inactivation (CDI) and induces calcium-dependent facilitation (CDF) through two structurally separable modules: the CaBP1 C-lobe anchors to the CaV1.2 IQ domain (overlapping with Ca2+/CaM C-lobe binding site), while the N-lobe together with interlobe linker residue Glu94 mediates CDI inhibition and CDF. Unlike CaM, functional CaBP1 EF-hands are not required for CDI inhibition.","method":"Crystal/structural analysis, electrophysiology, mutagenesis, binding assays","journal":"Structure (London, England : 1993)","confidence":"High","confidence_rationale":"Tier 1 / Moderate — structural data plus electrophysiology and mutagenesis in one study establishing domain-function separation","pmids":["21134641"],"is_preprint":false},{"year":2013,"finding":"CaM and CaBP1 compete directly for the CaV1 IQ domain via their apo (Ca2+-free) states, and the ratio of their apo-state binding affinities quantitatively predicts the functional outcome (CDI vs. CDI inhibition). Ca2+/CaM achieves sub-picomolar affinity for the IQ domain. Covalent tethering of CaM to the channel completely blocks this competition.","method":"Isothermal titration calorimetry, cell-based electrophysiology, mathematical modeling, covalent CaM tethering","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — ITC binding measurements, functional electrophysiology, and mathematical modeling with a mechanistic tethering control; multiple orthogonal methods in one lab","pmids":["23811053"],"is_preprint":false},{"year":2011,"finding":"CaBP1 interacts with the distal third of the CaV1.2 α1C N-terminal domain in a Ca2+-independent manner (distinct from the calmodulin-binding site in the N-terminus). CaBP1 also enhances voltage-dependent inactivation (VDI) and causes a depolarizing shift in voltage-dependent activation of CaV1.2. A proximal N-terminal segment separate from the CaBP1-binding site is required for transduction of the VDI effect, indicating modular organization of the N-terminal domain.","method":"Pull-down binding assays, electrophysiology of alternatively spliced CaV1.2 isoforms, deletion analysis","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal binding assays plus electrophysiology with deletion mutants; single lab, two orthogonal methods","pmids":["21383011"],"is_preprint":false},{"year":2007,"finding":"CaBP1 binds to the IQ motifs in the myo1c regulatory domain, competing with calmodulin for these sites; CaBP1 has higher apparent affinity for myo1c than CIB1, and both proteins compete better with calmodulin in the presence of calcium. CaBP1 and myo1c colocalize in cells as shown by fluorescence microscopy, and their interaction was confirmed by pull-down experiments with endogenous proteins.","method":"Pull-down assays, fluorescence microscopy colocalization, competition binding assays","journal":"Journal of muscle research and cell motility","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — pull-down and colocalization in two orthogonal methods, single lab","pmids":["17994197"],"is_preprint":false},{"year":2006,"finding":"L-CaBP1 (the long isoform of neuronal CaBP1) pulls down ARF1, Ca2+-dependent activator protein for secretion 1 (CAPS1), cyclic nucleotide 3′,5′-phosphodiesterase, vacuolar ATPase, AP1 and AP2 complexes, and the type I TGF-β receptor from bovine brain extracts in a Ca2+-dependent manner; some interactions were specific to CaBP1 and did not overlap with known calmodulin-binding proteins.","method":"GST pull-down from bovine brain cytosol/membrane extracts, MALDI-MS, Western blotting","journal":"Proteomics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single pull-down screen, single lab, no functional validation of individual interactions","pmids":["16470652"],"is_preprint":false},{"year":2018,"finding":"In cochlear spiral ganglion neurons (SGNs) from CaBP1 knockout mice, CaV1 (L-type) Ca2+ currents exhibit greater Ca2+-dependent inactivation (CDI) than wild-type, confirming that endogenous CaBP1 suppresses CDI of CaV1 channels in native neurons. Loss of CaBP1 also blunts activity-dependent repression of neurite growth and reduces CaV1-mediated phosphorylation of CREB, establishing that CaBP1 couples CaV1 channel activity to downstream transcriptional signaling.","method":"Whole-cell patch clamp electrophysiology in CaBP1 KO SGNs, neurite growth assays, CREB phosphorylation measurements","journal":"Molecular and cellular neurosciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean genetic KO with defined cellular phenotypes across multiple readouts (CDI, neurite growth, CREB phosphorylation); single lab","pmids":["29548764"],"is_preprint":false},{"year":2018,"finding":"In CaBP1 KO mice, auditory brainstem response (ABR) wave I is larger in amplitude and shorter in latency, consistent with enhanced synchrony of auditory nerve fibers, and spiral ganglion neurons show greater excitability in patch-clamp recordings. Normal presynaptic function of inner hair cells is retained in CaBP1 KO mice, suggesting CaBP1 acts postsynaptically in spiral ganglion neurons rather than at the IHC presynapse.","method":"ABR recordings, whole-cell patch clamp of spiral ganglion neurons, auditory physiology in KO mice","journal":"Hearing research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with in vivo ABR and ex vivo patch clamp; single lab, two orthogonal methods","pmids":["29661613"],"is_preprint":false},{"year":2024,"finding":"CaBP1 and CaBP2 act cooperatively to suppress both voltage-dependent and calcium-dependent inactivation of CaV1.3 channels in inner hair cells (IHCs). In Cabp1/2 double-knockout mice, CaV1.3 inactivation is strongly enhanced, recovery from inactivation is slowed, and sustained exocytosis is severely impaired; transgenic re-expression of CaBP2 alone substantially rescues IHC synaptic function and hearing, demonstrating partial functional redundancy.","method":"Patch-clamp electrophysiology (CaV1.3 current recordings), exocytosis measurements, in vivo auditory recordings in double-KO and rescue transgenic mice","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — double-KO with transgenic rescue, multiple electrophysiology readouts, in vivo and ex vivo convergent results across IHC function and hearing","pmids":["39718549"],"is_preprint":false},{"year":2016,"finding":"CaBP1/caldendrin knockout mice show altered retinal ganglion cell light responses (differences in amplitude and kinetics) despite normal gross retinal morphology, normal synapse ribbon counts, and normal ribbon synapse ultrastructure, indicating CaBP1/caldendrin is required for proper transmission of light responses through the retina, likely via presynaptic Ca2+-dependent signaling modulation.","method":"Whole-cell patch clamp of retinal ganglion cells in Cabp1 KO mice, immunohistochemistry, transmission electron microscopy","journal":"eNeuro","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with electrophysiology and ultrastructural controls; single lab, two orthogonal methods","pmids":["27822497"],"is_preprint":false},{"year":2026,"finding":"NMR structures of Ca2+-CaBP1 bound to the CaV1.2 IQ-motif peptide identify specific contact residues: CaBP1 residues A107, F111, M128, L131, I144, and M165 contact IQ residues I1654, Y1657, and F1658, with a salt bridge between IQ K1662 and CaBP1 D140. Ca2+ binding to CaBP1 is enhanced >40-fold when CaBP1 is bound to the IQ peptide; the IQ peptide binds Ca2+-bound CaBP1 with ~100-fold higher affinity (Kd ~45 nM) than Ca2+-free CaBP1. Electrophysiology suggests CaBP1 increases CaV1.2 channel open probability.","method":"NMR structure determination, ITC binding assays, mutagenesis (K1662 charge reversal), electrophysiology","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — NMR structure with atomic-resolution contacts, ITC binding quantification, mutagenesis validation, and electrophysiology; multiple orthogonal methods in one study","pmids":["41859936"],"is_preprint":false}],"current_model":"CaBP1 (CABP1) is a neuron-specific EF-hand Ca2+-binding protein that constitutively binds Mg2+ at EF-1 and cooperatively binds Ca2+ at EF-3/EF-4, switching between structurally distinct conformational states; in its Ca2+-bound form it competitively displaces calmodulin from the IQ-motif of CaV1 (L-type) voltage-gated Ca2+ channels to block Ca2+-dependent inactivation and promote Ca2+-dependent facilitation (increasing channel open probability), while also binding the N-terminal suppressor and ligand-binding core domains of InsP3R1 to clamp intersubunit movements and inhibit InsP3-evoked Ca2+ release; in inner hair cells CaBP1 and CaBP2 cooperate to suppress CaV1.3 inactivation and sustain exocytosis for sound encoding, and in neurons CaBP1 couples CaV1 activity to downstream CREB phosphorylation and activity-dependent neurite growth regulation."},"narrative":{"mechanistic_narrative":"CaBP1 (caldendrin) is a neuronal EF-hand Ca2+-binding protein that acts as a bifunctional Ca2+ sensor regulating voltage-gated Ca2+ channels and intracellular Ca2+-release channels to shape activity-dependent neuronal signaling [PMID:16147998, PMID:29548764]. It binds Mg2+ constitutively at EF-1 and Ca2+ cooperatively at EF-3/EF-4, with Mg2+ and Ca2+ stabilizing distinct conformational states; the C-domain undergoes a calmodulin-like closed-to-open transition upon Ca2+ binding while the N-domain remains closed with Mg2+ at EF-1 [PMID:16147998, PMID:19008222]. Through its C-lobe, Ca2+-CaBP1 binds the N-terminal suppressor and InsP3-binding core domains of InsP3R1 and clamps the intersubunit interface that InsP3 must disrupt to gate the channel, thereby inhibiting InsP3-evoked Ca2+ release [PMID:19008222, PMID:23650371]. At CaV1 (L-type) channels, CaBP1 anchors its C-lobe to the IQ domain — overlapping the Ca2+/CaM site — while N-lobe and interlobe linker residues mediate suppression of Ca2+-dependent inactivation; CaBP1 and CaM compete for the IQ motif through their apo states, and atomic-resolution structures define the IQ contacts and show CaBP1 raises channel open probability [PMID:21134641, PMID:23811053, PMID:41859936]. CaBP1 additionally engages the CaV1.2 N-terminal domain in a Ca2+-independent manner to modulate voltage-dependent gating [PMID:21383011]. In native neurons, endogenous CaBP1 suppresses CaV1 inactivation and couples channel activity to CREB phosphorylation and activity-dependent neurite-growth control [PMID:29548764], and in the auditory and visual systems CaBP1 (cooperatively with CaBP2 in inner hair cells) sustains Ca2+ signaling required for sound encoding and retinal light-response transmission [PMID:39718549, PMID:27822497].","teleology":[{"year":2005,"claim":"Establishing the metal-binding logic of CaBP1 answered how it could function as a Ca2+ sensor with a non-canonical EF-hand array.","evidence":"NMR, ITC, and thermal stability analyses of recombinant CaBP1","pmids":["16147998"],"confidence":"High","gaps":["Did not establish which downstream targets read out the Mg2+ vs Ca2+ states","Functional consequence of dimerization in cells unresolved"]},{"year":2008,"claim":"Solving the two-state structures and identifying InsP3R1 binding linked CaBP1's conformational switch to a defined effector domain.","evidence":"NMR structure determination of Mg2+- and Ca2+-bound CaBP1 plus ITC binding to InsP3R1 fragments","pmids":["19008222"],"confidence":"High","gaps":["Did not resolve how binding alters InsP3R gating","C-domain vs N-domain contributions to channel regulation not yet functionally tested"]},{"year":2010,"claim":"Mapping separable CaBP1 modules to the CaV1.2 IQ domain explained how CaBP1 both anchors to and functionally inverts the calmodulin regulatory site.","evidence":"Structural analysis, electrophysiology, and mutagenesis of CaV1.2","pmids":["21134641"],"confidence":"High","gaps":["Why functional EF-hands are dispensable for CDI inhibition not fully explained","In vivo relevance not addressed"]},{"year":2011,"claim":"Identifying a Ca2+-independent CaBP1 contact on the CaV1.2 N-terminus revealed a second, modular regulatory site distinct from the IQ/CaM axis.","evidence":"Pull-down binding assays and electrophysiology of spliced CaV1.2 isoforms with deletions","pmids":["21383011"],"confidence":"Medium","gaps":["Single-lab finding without structural detail","Interplay between N-terminal and IQ-domain effects unresolved"]},{"year":2013,"claim":"Defining the InsP3R inhibition mechanism and the apo-state CaM/CaBP1 competition unified how CaBP1 controls both release and channel inactivation.","evidence":"NMR PRE, cross-linking and Ca2+-flux assays for InsP3R; ITC, electrophysiology, modeling and CaM-tethering for CaV1 IQ competition","pmids":["23650371","23811053"],"confidence":"High","gaps":["Quantitative apo-affinity ratios measured in vitro; cellular concentrations setting the balance not determined","Whether the InsP3R and CaV1 regulatory modes operate simultaneously in the same cell unaddressed"]},{"year":2018,"claim":"Knockout studies in spiral ganglion neurons proved endogenous CaBP1 suppresses CaV1 inactivation and links channel activity to CREB and neurite growth in native cells.","evidence":"Patch clamp, neurite growth assays, CREB phosphorylation, and ABR recordings in CaBP1 KO mice","pmids":["29548764","29661613"],"confidence":"Medium","gaps":["Did not separate postsynaptic from presynaptic contributions at the molecular level","Transcriptional targets downstream of CREB not defined"]},{"year":2016,"claim":"Retinal knockout phenotypes extended CaBP1's role to sensory transmission, showing it is required for normal light-response kinetics independent of synaptic ultrastructure.","evidence":"Patch clamp of retinal ganglion cells, immunohistochemistry, and electron microscopy in Cabp1 KO mice","pmids":["27822497"],"confidence":"Medium","gaps":["Specific channel target in retina not pinpointed","Pre- vs postsynaptic site of action inferred, not directly demonstrated"]},{"year":2024,"claim":"Double-knockout and rescue experiments established functional cooperativity and partial redundancy between CaBP1 and CaBP2 in suppressing CaV1.3 inactivation for hearing.","evidence":"Patch clamp, exocytosis measurements, and in vivo auditory recordings in Cabp1/2 double-KO and CaBP2 rescue mice","pmids":["39718549"],"confidence":"High","gaps":["Degree of CaBP1-specific (non-redundant) function not isolated","Molecular basis of cooperativity between the two paralogs unresolved"]},{"year":2026,"claim":"Atomic-resolution structure of Ca2+-CaBP1 on the CaV1.2 IQ peptide defined the binding interface and showed reciprocal enhancement of Ca2+ and peptide affinity, linking conformation to increased channel open probability.","evidence":"NMR structure, ITC, charge-reversal mutagenesis, and electrophysiology","pmids":["41859936"],"confidence":"High","gaps":["How open-probability change relates mechanistically to CDI suppression not fully integrated","Full-length channel structure with bound CaBP1 not determined"]},{"year":null,"claim":"How CaBP1's competing roles at CaV channels, InsP3R, and other IQ-motif partners are coordinated within a single neuron and across cell types remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model of target selection in vivo","Stoichiometry and local Ca2+/CaM competition in native cells unmeasured","Significance of brain interactors from pull-down screens not functionally established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[2,3,4,8,10]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[8]}],"localization":[],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,3,8]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[8,9,10,11]}],"complexes":[],"partners":["CACNA1C","CACNA1D","ITPR1","CALM1","MYO1C","CABP2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9NZU7","full_name":"Calcium-binding protein 1","aliases":["Calbrain","Caldendrin"],"length_aa":370,"mass_kda":39.8,"function":"Modulates calcium-dependent activity of inositol 1,4,5-triphosphate receptors (ITPRs) (PubMed:14570872). Inhibits agonist-induced intracellular calcium signaling (PubMed:15980432). Enhances inactivation and does not support calcium-dependent facilitation of voltage-dependent P/Q-type calcium channels (PubMed:11865310). Causes calcium-dependent facilitation and inhibits inactivation of L-type calcium channels by binding to the same sites as calmodulin in the C-terminal domain of CACNA1C, but has an opposite effect on channel function (PubMed:15140941). Suppresses the calcium-dependent inactivation of CACNA1D (By similarity). Inhibits TRPC5 channels (PubMed:15895247). Prevents NMDA receptor-induced cellular degeneration. Required for the normal transfer of light signals through the retina (By similarity)","subcellular_location":"Cytoplasm, cell cortex; Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q9NZU7/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CABP1","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CABP1","total_profiled":1310},"omim":[{"mim_id":"618759","title":"CALCIUM-BINDING PROTEIN 7; CABP7","url":"https://www.omim.org/entry/618759"},{"mim_id":"607315","title":"CALCIUM-BINDING PROTEIN 5; CABP5","url":"https://www.omim.org/entry/607315"},{"mim_id":"607314","title":"CALCIUM-BINDING PROTEIN 2; CABP2","url":"https://www.omim.org/entry/607314"},{"mim_id":"605563","title":"CALCIUM-BINDING PROTEIN 1; CABP1","url":"https://www.omim.org/entry/605563"},{"mim_id":"602293","title":"CALCIUM- AND INTEGRIN-BINDING PROTEIN 1; CIB1","url":"https://www.omim.org/entry/602293"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"brain","ntpm":419.6}],"url":"https://www.proteinatlas.org/search/CABP1"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"Q9NZU7","domains":[{"cath_id":"1.10.238.10","chopping":"220-298","consensus_level":"medium","plddt":76.1135,"start":220,"end":298},{"cath_id":"1.10.238.10","chopping":"299-370","consensus_level":"medium","plddt":79.3607,"start":299,"end":370}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NZU7","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NZU7-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NZU7-F1-predicted_aligned_error_v6.png","plddt_mean":58.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CABP1","jax_strain_url":"https://www.jax.org/strain/search?query=CABP1"},"sequence":{"accession":"Q9NZU7","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9NZU7.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9NZU7/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NZU7"}},"corpus_meta":[{"pmid":"8300576","id":"PMC_8300576","title":"Effects of CaBP2, the rat analog of ERp72, and of CaBP1 on the refolding of denatured reduced proteins. Comparison with protein disulfide isomerase.","date":"1994","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/8300576","citation_count":77,"is_preprint":false},{"pmid":"16147998","id":"PMC_16147998","title":"Structural analysis of Mg2+ and Ca2+ binding to CaBP1, a neuron-specific regulator of calcium channels.","date":"2005","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/16147998","citation_count":73,"is_preprint":false},{"pmid":"7835433","id":"PMC_7835433","title":"Two resident ER-proteins, CaBP1 and CaBP2, with thioredoxin domains, are substrates for thioredoxin reductase: comparison with protein disulfide isomerase.","date":"1995","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/7835433","citation_count":73,"is_preprint":false},{"pmid":"19008222","id":"PMC_19008222","title":"Structural insights into Ca2+-dependent regulation of inositol 1,4,5-trisphosphate receptors by CaBP1.","date":"2008","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/19008222","citation_count":53,"is_preprint":false},{"pmid":"21134641","id":"PMC_21134641","title":"Structural basis for the differential effects of CaBP1 and calmodulin on Ca(V)1.2 calcium-dependent inactivation.","date":"2010","source":"Structure (London, England : 1993)","url":"https://pubmed.ncbi.nlm.nih.gov/21134641","citation_count":52,"is_preprint":false},{"pmid":"16470652","id":"PMC_16470652","title":"Analysis of the interacting partners of the neuronal calcium-binding proteins L-CaBP1, hippocalcin, NCS-1 and neurocalcin delta.","date":"2006","source":"Proteomics","url":"https://pubmed.ncbi.nlm.nih.gov/16470652","citation_count":50,"is_preprint":false},{"pmid":"23811053","id":"PMC_23811053","title":"Apo states of calmodulin and CaBP1 control CaV1 voltage-gated calcium channel function through direct competition for the IQ domain.","date":"2013","source":"Journal of 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transmission in inner hair cells.","date":"2024","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/39718549","citation_count":8,"is_preprint":false},{"pmid":"29548764","id":"PMC_29548764","title":"CaBP1 regulates Cav1 L-type Ca2+ channels and their coupling to neurite growth and gene transcription in mouse spiral ganglion neurons.","date":"2018","source":"Molecular and cellular neurosciences","url":"https://pubmed.ncbi.nlm.nih.gov/29548764","citation_count":8,"is_preprint":false},{"pmid":"9770267","id":"PMC_9770267","title":"A homologue of the calcium-binding disulfide isomerase CaBP1 is expressed in the developing CNS of Drosophila melanogaster.","date":"1998","source":"Developmental genetics","url":"https://pubmed.ncbi.nlm.nih.gov/9770267","citation_count":3,"is_preprint":false},{"pmid":"19636926","id":"PMC_19636926","title":"1H, 15N, and 13C chemical shift assignments of calcium-bound calcium-binding protein 1 (CaBP1).","date":"2008","source":"Biomolecular NMR assignments","url":"https://pubmed.ncbi.nlm.nih.gov/19636926","citation_count":3,"is_preprint":false},{"pmid":"19636832","id":"PMC_19636832","title":"1H, 15N, and 13C chemical shift assignments of calcium-binding protein 1 (CaBP1).","date":"2007","source":"Biomolecular NMR assignments","url":"https://pubmed.ncbi.nlm.nih.gov/19636832","citation_count":2,"is_preprint":false},{"pmid":"36064846","id":"PMC_36064846","title":"Chemical shift assignments of the C-terminal domain of CaBP1 bound to the IQ-motif of voltage-gated Ca2+ channel (CaV1.2).","date":"2022","source":"Biomolecular NMR assignments","url":"https://pubmed.ncbi.nlm.nih.gov/36064846","citation_count":1,"is_preprint":false},{"pmid":"1989693","id":"PMC_1989693","title":"A 27-bp deletion is responsible for the expression of a variant CABP1, a cyclic AMP-binding protein of Dictyostelium discoideum.","date":"1991","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/1989693","citation_count":1,"is_preprint":false},{"pmid":"41859936","id":"PMC_41859936","title":"Structural Insights into L-Type Voltage-Gated Ca2+ Channel (CaV1.2) Activation by CaBP1.","date":"2026","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/41859936","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.10.24.684426","title":"Pleckstrin homology domain-containing serine/threonine kinase plays a crucial role in the survival and phagocytosis of  <i>Entamoeba histolytica</i>","date":"2025-10-26","source":"bioRxiv","url":"https://doi.org/10.1101/2025.10.24.684426","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":13974,"output_tokens":4358,"usd":0.053646,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11632,"output_tokens":3171,"usd":0.068718,"stage2_stop_reason":"end_turn"},"total_usd":0.122364,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","note":"batch pricing = 50% of standard"},"stage1_raw":"I need to carefully classify each paper before extracting discoveries.\n\n**Classification notes:**\n- Papers [1], [3], [10], [17], [20]: These describe a rat/mammalian ER-resident protein called \"CaBP1\" that is a PDI family member with thioredoxin domains. This is a DIFFERENT protein from the neuronal EF-hand calcium sensor CaBP1 (HGNC: CABP1). The rat \"CaBP1\" is P5/PDIA6, not CABP1. However, I need to check if CABP1 aliases include P5 — the corpus context strongly indicates two distinct proteins share the \"CaBP1\" name. The neuronal CABP1 is a 19.4 kDa EF-hand protein; the ER CaBP1 is a 440 aa PDI family protein. These are clearly different genes.\n- Papers [14], [24]: Dictyostelium CABP1 — cAMP-binding protein, clearly a symbol collision.\n- Paper [26]: Entamoeba EhCaBP1 — symbol collision, different organism/protein.\n- Papers [2], [4], [5], [7], [8], [9], [12], [13], [15], [16], [18], [19], [21], [22], [23], [25]: These describe the neuronal EF-hand Ca2+-binding protein CaBP1 (CABP1) — the canonical query gene.\n- Paper [6]: Describes L-CaBP1 as an EF-hand neuronal calcium sensor — this is the canonical CABP1.\n- Paper [11]: CaBP1/caldendrin in mouse brain — canonical CABP1.\n\nPapers [1], [3], [10], [17], [20] describe the ER PDI-family CaBP1 (rat P5/PDIA6) — EXCLUDE as alias collision.\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2005,\n      \"finding\": \"CaBP1 binds Mg2+ constitutively at EF-1 (Kd ~300 µM) and binds Ca2+ cooperatively at EF-3 and EF-4 (Kd ~2.5 µM); no Ca2+ binding detected at EF-2. Mg2+ and Ca2+ induce distinct conformational changes that promote protein dimerization and increased folding stability, suggesting CaBP1 switches between structurally distinct Mg2+-bound and Ca2+-bound states in response to Ca2+ signaling.\",\n      \"method\": \"NMR spectroscopy, isothermal titration calorimetry (ITC), and other biophysical analyses of recombinant CaBP1\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal biophysical methods (NMR, ITC, thermal stability) in a single rigorous study, with site-specific resolution of each EF-hand\",\n      \"pmids\": [\"16147998\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"NMR structures of CaBP1 in Mg2+-bound and Ca2+-bound states show the N-domain (EF1/EF2) adopts a closed conformation with Mg2+ at EF1, while the C-domain undergoes a Ca2+-induced closed-to-open transition (like calmodulin), exposing hydrophobic residues (Leu132, His134, Ile141, Ile144, Val148). Ca2+-bound CaBP1 C-domain binds the N-terminal suppressor and ligand-binding core domains of InsP3R1 (residues 1–587) via ITC, whereas the CaBP1 N-domain and calmodulin did not show appreciable binding under these conditions.\",\n      \"method\": \"NMR structure determination, isothermal titration calorimetry\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — NMR structures of two states plus ITC binding measurements, multiple orthogonal methods in one study\",\n      \"pmids\": [\"19008222\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CaBP1 inhibits InsP3R activity by clamping intersubunit interactions: the CaBP1 C-lobe binds the β-domain of the InsP3-binding core of InsP3R1 via a hydrophobic cluster (V101, L104, V162 on CaBP1; L302, I364, L393 on InsP3R). CaBP1 promotes the intersubunit interface between the suppressor domain and the InsP3-binding core β-domain, the same interface that InsP3 disrupts to initiate gating. Thus CaBP1 slows InsP3R opening by restricting the conformational changes required for gating, and this inhibition is enhanced by Ca2+ binding to both CaBP1 and InsP3R.\",\n      \"method\": \"NMR paramagnetic relaxation enhancement, targeted cross-linking, Ca2+ flux assays, mutagenesis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — NMR PRE structural restraints, mutagenesis of key interface residues, cross-linking functional assay, and Ca2+ flux measurements; multiple orthogonal methods\",\n      \"pmids\": [\"23650371\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"CaBP1 inhibits CaV1.2 calcium-dependent inactivation (CDI) and induces calcium-dependent facilitation (CDF) through two structurally separable modules: the CaBP1 C-lobe anchors to the CaV1.2 IQ domain (overlapping with Ca2+/CaM C-lobe binding site), while the N-lobe together with interlobe linker residue Glu94 mediates CDI inhibition and CDF. Unlike CaM, functional CaBP1 EF-hands are not required for CDI inhibition.\",\n      \"method\": \"Crystal/structural analysis, electrophysiology, mutagenesis, binding assays\",\n      \"journal\": \"Structure (London, England : 1993)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — structural data plus electrophysiology and mutagenesis in one study establishing domain-function separation\",\n      \"pmids\": [\"21134641\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CaM and CaBP1 compete directly for the CaV1 IQ domain via their apo (Ca2+-free) states, and the ratio of their apo-state binding affinities quantitatively predicts the functional outcome (CDI vs. CDI inhibition). Ca2+/CaM achieves sub-picomolar affinity for the IQ domain. Covalent tethering of CaM to the channel completely blocks this competition.\",\n      \"method\": \"Isothermal titration calorimetry, cell-based electrophysiology, mathematical modeling, covalent CaM tethering\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — ITC binding measurements, functional electrophysiology, and mathematical modeling with a mechanistic tethering control; multiple orthogonal methods in one lab\",\n      \"pmids\": [\"23811053\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"CaBP1 interacts with the distal third of the CaV1.2 α1C N-terminal domain in a Ca2+-independent manner (distinct from the calmodulin-binding site in the N-terminus). CaBP1 also enhances voltage-dependent inactivation (VDI) and causes a depolarizing shift in voltage-dependent activation of CaV1.2. A proximal N-terminal segment separate from the CaBP1-binding site is required for transduction of the VDI effect, indicating modular organization of the N-terminal domain.\",\n      \"method\": \"Pull-down binding assays, electrophysiology of alternatively spliced CaV1.2 isoforms, deletion analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal binding assays plus electrophysiology with deletion mutants; single lab, two orthogonal methods\",\n      \"pmids\": [\"21383011\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"CaBP1 binds to the IQ motifs in the myo1c regulatory domain, competing with calmodulin for these sites; CaBP1 has higher apparent affinity for myo1c than CIB1, and both proteins compete better with calmodulin in the presence of calcium. CaBP1 and myo1c colocalize in cells as shown by fluorescence microscopy, and their interaction was confirmed by pull-down experiments with endogenous proteins.\",\n      \"method\": \"Pull-down assays, fluorescence microscopy colocalization, competition binding assays\",\n      \"journal\": \"Journal of muscle research and cell motility\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — pull-down and colocalization in two orthogonal methods, single lab\",\n      \"pmids\": [\"17994197\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"L-CaBP1 (the long isoform of neuronal CaBP1) pulls down ARF1, Ca2+-dependent activator protein for secretion 1 (CAPS1), cyclic nucleotide 3′,5′-phosphodiesterase, vacuolar ATPase, AP1 and AP2 complexes, and the type I TGF-β receptor from bovine brain extracts in a Ca2+-dependent manner; some interactions were specific to CaBP1 and did not overlap with known calmodulin-binding proteins.\",\n      \"method\": \"GST pull-down from bovine brain cytosol/membrane extracts, MALDI-MS, Western blotting\",\n      \"journal\": \"Proteomics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single pull-down screen, single lab, no functional validation of individual interactions\",\n      \"pmids\": [\"16470652\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"In cochlear spiral ganglion neurons (SGNs) from CaBP1 knockout mice, CaV1 (L-type) Ca2+ currents exhibit greater Ca2+-dependent inactivation (CDI) than wild-type, confirming that endogenous CaBP1 suppresses CDI of CaV1 channels in native neurons. Loss of CaBP1 also blunts activity-dependent repression of neurite growth and reduces CaV1-mediated phosphorylation of CREB, establishing that CaBP1 couples CaV1 channel activity to downstream transcriptional signaling.\",\n      \"method\": \"Whole-cell patch clamp electrophysiology in CaBP1 KO SGNs, neurite growth assays, CREB phosphorylation measurements\",\n      \"journal\": \"Molecular and cellular neurosciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean genetic KO with defined cellular phenotypes across multiple readouts (CDI, neurite growth, CREB phosphorylation); single lab\",\n      \"pmids\": [\"29548764\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"In CaBP1 KO mice, auditory brainstem response (ABR) wave I is larger in amplitude and shorter in latency, consistent with enhanced synchrony of auditory nerve fibers, and spiral ganglion neurons show greater excitability in patch-clamp recordings. Normal presynaptic function of inner hair cells is retained in CaBP1 KO mice, suggesting CaBP1 acts postsynaptically in spiral ganglion neurons rather than at the IHC presynapse.\",\n      \"method\": \"ABR recordings, whole-cell patch clamp of spiral ganglion neurons, auditory physiology in KO mice\",\n      \"journal\": \"Hearing research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with in vivo ABR and ex vivo patch clamp; single lab, two orthogonal methods\",\n      \"pmids\": [\"29661613\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CaBP1 and CaBP2 act cooperatively to suppress both voltage-dependent and calcium-dependent inactivation of CaV1.3 channels in inner hair cells (IHCs). In Cabp1/2 double-knockout mice, CaV1.3 inactivation is strongly enhanced, recovery from inactivation is slowed, and sustained exocytosis is severely impaired; transgenic re-expression of CaBP2 alone substantially rescues IHC synaptic function and hearing, demonstrating partial functional redundancy.\",\n      \"method\": \"Patch-clamp electrophysiology (CaV1.3 current recordings), exocytosis measurements, in vivo auditory recordings in double-KO and rescue transgenic mice\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — double-KO with transgenic rescue, multiple electrophysiology readouts, in vivo and ex vivo convergent results across IHC function and hearing\",\n      \"pmids\": [\"39718549\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CaBP1/caldendrin knockout mice show altered retinal ganglion cell light responses (differences in amplitude and kinetics) despite normal gross retinal morphology, normal synapse ribbon counts, and normal ribbon synapse ultrastructure, indicating CaBP1/caldendrin is required for proper transmission of light responses through the retina, likely via presynaptic Ca2+-dependent signaling modulation.\",\n      \"method\": \"Whole-cell patch clamp of retinal ganglion cells in Cabp1 KO mice, immunohistochemistry, transmission electron microscopy\",\n      \"journal\": \"eNeuro\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with electrophysiology and ultrastructural controls; single lab, two orthogonal methods\",\n      \"pmids\": [\"27822497\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"NMR structures of Ca2+-CaBP1 bound to the CaV1.2 IQ-motif peptide identify specific contact residues: CaBP1 residues A107, F111, M128, L131, I144, and M165 contact IQ residues I1654, Y1657, and F1658, with a salt bridge between IQ K1662 and CaBP1 D140. Ca2+ binding to CaBP1 is enhanced >40-fold when CaBP1 is bound to the IQ peptide; the IQ peptide binds Ca2+-bound CaBP1 with ~100-fold higher affinity (Kd ~45 nM) than Ca2+-free CaBP1. Electrophysiology suggests CaBP1 increases CaV1.2 channel open probability.\",\n      \"method\": \"NMR structure determination, ITC binding assays, mutagenesis (K1662 charge reversal), electrophysiology\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — NMR structure with atomic-resolution contacts, ITC binding quantification, mutagenesis validation, and electrophysiology; multiple orthogonal methods in one study\",\n      \"pmids\": [\"41859936\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CaBP1 (CABP1) is a neuron-specific EF-hand Ca2+-binding protein that constitutively binds Mg2+ at EF-1 and cooperatively binds Ca2+ at EF-3/EF-4, switching between structurally distinct conformational states; in its Ca2+-bound form it competitively displaces calmodulin from the IQ-motif of CaV1 (L-type) voltage-gated Ca2+ channels to block Ca2+-dependent inactivation and promote Ca2+-dependent facilitation (increasing channel open probability), while also binding the N-terminal suppressor and ligand-binding core domains of InsP3R1 to clamp intersubunit movements and inhibit InsP3-evoked Ca2+ release; in inner hair cells CaBP1 and CaBP2 cooperate to suppress CaV1.3 inactivation and sustain exocytosis for sound encoding, and in neurons CaBP1 couples CaV1 activity to downstream CREB phosphorylation and activity-dependent neurite growth regulation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CaBP1 (caldendrin) is a neuronal EF-hand Ca2+-binding protein that acts as a bifunctional Ca2+ sensor regulating voltage-gated Ca2+ channels and intracellular Ca2+-release channels to shape activity-dependent neuronal signaling [#0, #8]. It binds Mg2+ constitutively at EF-1 and Ca2+ cooperatively at EF-3/EF-4, with Mg2+ and Ca2+ stabilizing distinct conformational states; the C-domain undergoes a calmodulin-like closed-to-open transition upon Ca2+ binding while the N-domain remains closed with Mg2+ at EF-1 [#0, #1]. Through its C-lobe, Ca2+-CaBP1 binds the N-terminal suppressor and InsP3-binding core domains of InsP3R1 and clamps the intersubunit interface that InsP3 must disrupt to gate the channel, thereby inhibiting InsP3-evoked Ca2+ release [#1, #2]. At CaV1 (L-type) channels, CaBP1 anchors its C-lobe to the IQ domain — overlapping the Ca2+/CaM site — while N-lobe and interlobe linker residues mediate suppression of Ca2+-dependent inactivation; CaBP1 and CaM compete for the IQ motif through their apo states, and atomic-resolution structures define the IQ contacts and show CaBP1 raises channel open probability [#3, #4, #12]. CaBP1 additionally engages the CaV1.2 N-terminal domain in a Ca2+-independent manner to modulate voltage-dependent gating [#5]. In native neurons, endogenous CaBP1 suppresses CaV1 inactivation and couples channel activity to CREB phosphorylation and activity-dependent neurite-growth control [#8], and in the auditory and visual systems CaBP1 (cooperatively with CaBP2 in inner hair cells) sustains Ca2+ signaling required for sound encoding and retinal light-response transmission [#10, #11].\",\n  \"teleology\": [\n    {\n      \"year\": 2005,\n      \"claim\": \"Establishing the metal-binding logic of CaBP1 answered how it could function as a Ca2+ sensor with a non-canonical EF-hand array.\",\n      \"evidence\": \"NMR, ITC, and thermal stability analyses of recombinant CaBP1\",\n      \"pmids\": [\"16147998\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish which downstream targets read out the Mg2+ vs Ca2+ states\", \"Functional consequence of dimerization in cells unresolved\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Solving the two-state structures and identifying InsP3R1 binding linked CaBP1's conformational switch to a defined effector domain.\",\n      \"evidence\": \"NMR structure determination of Mg2+- and Ca2+-bound CaBP1 plus ITC binding to InsP3R1 fragments\",\n      \"pmids\": [\"19008222\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve how binding alters InsP3R gating\", \"C-domain vs N-domain contributions to channel regulation not yet functionally tested\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Mapping separable CaBP1 modules to the CaV1.2 IQ domain explained how CaBP1 both anchors to and functionally inverts the calmodulin regulatory site.\",\n      \"evidence\": \"Structural analysis, electrophysiology, and mutagenesis of CaV1.2\",\n      \"pmids\": [\"21134641\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Why functional EF-hands are dispensable for CDI inhibition not fully explained\", \"In vivo relevance not addressed\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Identifying a Ca2+-independent CaBP1 contact on the CaV1.2 N-terminus revealed a second, modular regulatory site distinct from the IQ/CaM axis.\",\n      \"evidence\": \"Pull-down binding assays and electrophysiology of spliced CaV1.2 isoforms with deletions\",\n      \"pmids\": [\"21383011\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab finding without structural detail\", \"Interplay between N-terminal and IQ-domain effects unresolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Defining the InsP3R inhibition mechanism and the apo-state CaM/CaBP1 competition unified how CaBP1 controls both release and channel inactivation.\",\n      \"evidence\": \"NMR PRE, cross-linking and Ca2+-flux assays for InsP3R; ITC, electrophysiology, modeling and CaM-tethering for CaV1 IQ competition\",\n      \"pmids\": [\"23650371\", \"23811053\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Quantitative apo-affinity ratios measured in vitro; cellular concentrations setting the balance not determined\", \"Whether the InsP3R and CaV1 regulatory modes operate simultaneously in the same cell unaddressed\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Knockout studies in spiral ganglion neurons proved endogenous CaBP1 suppresses CaV1 inactivation and links channel activity to CREB and neurite growth in native cells.\",\n      \"evidence\": \"Patch clamp, neurite growth assays, CREB phosphorylation, and ABR recordings in CaBP1 KO mice\",\n      \"pmids\": [\"29548764\", \"29661613\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not separate postsynaptic from presynaptic contributions at the molecular level\", \"Transcriptional targets downstream of CREB not defined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Retinal knockout phenotypes extended CaBP1's role to sensory transmission, showing it is required for normal light-response kinetics independent of synaptic ultrastructure.\",\n      \"evidence\": \"Patch clamp of retinal ganglion cells, immunohistochemistry, and electron microscopy in Cabp1 KO mice\",\n      \"pmids\": [\"27822497\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific channel target in retina not pinpointed\", \"Pre- vs postsynaptic site of action inferred, not directly demonstrated\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Double-knockout and rescue experiments established functional cooperativity and partial redundancy between CaBP1 and CaBP2 in suppressing CaV1.3 inactivation for hearing.\",\n      \"evidence\": \"Patch clamp, exocytosis measurements, and in vivo auditory recordings in Cabp1/2 double-KO and CaBP2 rescue mice\",\n      \"pmids\": [\"39718549\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Degree of CaBP1-specific (non-redundant) function not isolated\", \"Molecular basis of cooperativity between the two paralogs unresolved\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Atomic-resolution structure of Ca2+-CaBP1 on the CaV1.2 IQ peptide defined the binding interface and showed reciprocal enhancement of Ca2+ and peptide affinity, linking conformation to increased channel open probability.\",\n      \"evidence\": \"NMR structure, ITC, charge-reversal mutagenesis, and electrophysiology\",\n      \"pmids\": [\"41859936\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How open-probability change relates mechanistically to CDI suppression not fully integrated\", \"Full-length channel structure with bound CaBP1 not determined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How CaBP1's competing roles at CaV channels, InsP3R, and other IQ-motif partners are coordinated within a single neuron and across cell types remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model of target selection in vivo\", \"Stoichiometry and local Ca2+/CaM competition in native cells unmeasured\", \"Significance of brain interactors from pull-down screens not functionally established\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [2, 3, 4, 8, 10]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [8]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 3, 8]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [8, 9, 10, 11]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"CACNA1C\", \"CACNA1D\", \"ITPR1\", \"CALM1\", \"MYO1C\", \"CABP2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}