Affinage

CABP1

Calcium-binding protein 1 · UniProt Q9NZU7

Length
370 aa
Mass
39.8 kDa
Annotated
2026-04-28
25 papers in source corpus 15 papers cited in narrative 15 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CaBP1 is a neuronal calmodulin-related EF-hand calcium sensor that tunes the activity of voltage-gated calcium channels and inositol 1,4,5-trisphosphate receptors by competing with calmodulin for shared binding determinants. CaBP1 constitutively binds Mg²⁺ at EF-1 and cooperatively binds Ca²⁺ at EF-3/EF-4, with each ion inducing distinct conformational states: the Ca²⁺-loaded C-lobe opens to expose hydrophobic residues that anchor to the IQ domain of CaV1.2/CaV1.3 channels, blocking Ca²⁺-dependent inactivation and promoting facilitation through its N-lobe/linker module, while the same C-lobe surface contacts the InsP3-binding core β-domain of InsP3R1 to clamp intersubunit conformational changes and inhibit channel gating (PMID:16147998, PMID:19008222, PMID:21134641, PMID:23650371, PMID:41859936). Apo-CaBP1 and apo-calmodulin compete directly for the CaV1 IQ domain, with their relative affinities governing opposing modes of channel regulation (PMID:23811053). In vivo, CaBP1 suppresses CaV1 inactivation in cochlear neurons to sustain CaV1-dependent CREB signaling and neurite growth regulation, and cooperates with CaBP2 to maintain sustained exocytosis at inner hair cell synapses required for normal hearing (PMID:29548764, PMID:39718549).

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 2005 High

    Establishing how CaBP1 senses divalent cations resolved the question of which EF-hands are functional and showed that Mg²⁺ and Ca²⁺ drive the protein into structurally distinct states — a prerequisite for understanding how ion occupancy controls target selection.

    Evidence NMR, ITC, and thermal denaturation on recombinant CaBP1

    PMID:16147998

    Open questions at the time
    • No structural detail on how Mg²⁺-induced dimerization affects target binding
    • EF-hand mutations not tested in cellular context
  2. 2008 High

    Determining the NMR structures of Mg²⁺-bound and Ca²⁺-bound CaBP1 revealed that the Ca²⁺-loaded C-lobe opens to expose hydrophobic residues that bind the InsP3R1 suppressor–ligand-binding core without blocking InsP3 binding, establishing the structural basis for CaBP1–InsP3R interaction.

    Evidence NMR structure determination and ITC binding to InsP3R1 fragments

    PMID:19008222

    Open questions at the time
    • Full-length InsP3R context not addressed
    • Effect on InsP3R gating not yet measured in this study
  3. 2010 High

    Crystallography and electrophysiology defined a two-module mechanism for CaBP1 regulation of CaV1.2: the C-lobe anchors to the IQ domain while the N-lobe/linker module (Glu94) mediates suppression of Ca²⁺-dependent inactivation and induction of facilitation, establishing that functional EF-hands are dispensable for CDI inhibition.

    Evidence Crystal structure of CaBP1–CaV1.2 IQ complex, mutagenesis, whole-cell patch clamp

    PMID:21134641

    Open questions at the time
    • Mechanism of facilitation induction by N-lobe/linker not resolved at atomic detail
    • Role of CaBP1 dimerization in channel regulation unclear
  4. 2011 Medium

    Identification of a Ca²⁺-independent CaBP1 binding site on the CaV1.2 N-terminal domain, distinct from the IQ-domain site, showed that CaBP1 engages the channel at a second locus that influences voltage-dependent inactivation and activation gating.

    Evidence Pull-down with deletion mutants, electrophysiology

    PMID:21383011

    Open questions at the time
    • No structure of N-terminal domain complex
    • Relative contribution of N-terminal versus IQ-domain interaction in intact channel not quantified
  5. 2013 High

    Two complementary studies resolved the competitive mechanism at the CaV1 IQ domain and the inhibitory mechanism at InsP3R1: apo-CaBP1/apo-CaM competition for the IQ domain quantitatively explains opposing channel regulation, while CaBP1's C-lobe hydrophobic contacts with InsP3R β-domain residues clamp intersubunit movements to inhibit gating.

    Evidence ITC and covalent CaM-tethering electrophysiology for CaV1 competition; NMR PRE, docking, cross-linking, and functional InsP3R assays for InsP3R mechanism

    PMID:23650371 PMID:23811053

    Open questions at the time
    • Full tetrameric InsP3R architecture of CaBP1 complex not validated by cryo-EM
    • Kinetics of CaBP1–CaM exchange on the channel in situ unknown
  6. 2018 Medium

    CaBP1-knockout cochlear spiral ganglion neurons confirmed that CaBP1 suppresses CaV1 Ca²⁺-dependent inactivation in vivo and showed downstream consequences: impaired CaV1-mediated CREB phosphorylation and loss of activity-dependent neurite growth repression.

    Evidence Whole-cell patch clamp, neurite growth assays, CREB phosphorylation in CaBP1-KO neurons

    PMID:29548764

    Open questions at the time
    • Single neuron type studied
    • Contribution of CaBP1 versus CaBP2 not disambiguated in this system
  7. 2024 High

    Double-knockout of CaBP1 and CaBP2 in mice demonstrated cooperative and partially redundant suppression of CaV1.3 inactivation in inner hair cells, with loss causing impaired sustained exocytosis and deafness that is rescued by transgenic CaBP2, establishing a physiological requirement for CaBP-family regulation of CaV1.3 in hearing.

    Evidence Double-KO mouse electrophysiology, capacitance measurements, auditory nerve recordings, transgenic rescue

    PMID:39718549

    Open questions at the time
    • Specific structural determinants of CaBP1 versus CaBP2 functional differences on CaV1.3 not resolved
    • Whether CaBP1 alone is sufficient for hearing rescue not tested
  8. 2026 High

    Atomic-resolution NMR structures of Ca²⁺-CaBP1 bound to the CaV1.2 IQ peptide identified specific intermolecular contacts and a salt bridge, showed that Ca²⁺ binding to EF3/EF4 enhances IQ affinity >40-fold, and linked CaBP1 binding to increased channel open probability — completing the structural picture of C-lobe–IQ engagement.

    Evidence NMR structure, ITC, electrophysiology, mutagenesis

    PMID:41859936

    Open questions at the time
    • Structure captured on isolated IQ peptide, not full-length channel
    • Mechanism by which CaBP1 increases open probability versus blocking inactivation not delineated

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unknown how CaBP1 partitions between CaV channels and InsP3Rs within a single neuron, whether its dimerization state is regulated in vivo, and whether it has physiologically relevant targets beyond ion channels.
  • No in vivo imaging or quantification of CaBP1 target partitioning
  • Dimerization regulation unexplored in cellular context
  • Proteomics hits (ARF1, CAPS1, AP complexes) lack functional validation

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 5 GO:0008092 cytoskeletal protein binding 1
Localization
GO:0005829 cytosol 3
Pathway
R-HSA-162582 Signal Transduction 5 R-HSA-112316 Neuronal System 2
Partners
CABP2CACNA1CCACNA1DITPR1MYO1C

Evidence

Reading pass · 15 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2005 CaBP1 (neuronal EF-hand protein) binds Mg2+ constitutively at EF-1 (Kd ~300 µM) and Ca2+ cooperatively at EF-3 and EF-4 (Kd ~2.5 µM); apo-CaBP1 forms a molten-globule, while Mg2+ and Ca2+ induce distinct conformational changes including protein dimerization and increased folding stability. NMR, microcalorimetry (ITC), and biophysical studies on recombinant CaBP1 The Journal of biological chemistry High 16147998
2008 NMR structures of CaBP1 in Mg2+-bound and Ca2+-bound states show the N-domain (EF1/EF2) remains closed with Mg2+ at EF1, while the C-domain undergoes a Ca2+-induced closed-to-open transition exposing hydrophobic residues (Leu132, His134, Ile141, Ile144, Val148). The Ca2+-bound C-domain binds the N-terminal suppressor+ligand-binding core region of InsP3R1 (residues 1–587) without affecting InsP3 binding itself. NMR structure determination, ITC binding assays The Journal of biological chemistry High 19008222
2013 CaBP1 inhibits InsP3R activity by clamping intersubunit interactions: its C-lobe hydrophobic residues (V101, L104, V162) contact InsP3-binding core β-domain residues (L302, I364, L393) of InsP3R1, and CaBP1 promotes cross-linking at the suppressor–core domain interface that InsP3 disrupts during gating; CaBP1 forms an extended tetrameric turret at the cytosolic vestibule. NMR paramagnetic relaxation enhancement, docking, targeted cross-linking, functional IP3R activity assays Proceedings of the National Academy of Sciences of the United States of America High 23650371
2010 CaBP1 modulates CaV1.2 through two structural modules: the C-lobe anchors to the CaV1.2 IQ domain (overlapping with Ca2+/CaM C-lobe site), while the N-lobe/linker module (specifically interlobe linker residue Glu94) mediates inhibition of Ca2+-dependent inactivation (CDI) and induction of Ca2+-dependent facilitation (CDF); functional EF-hands are not required for CDI inhibition unlike CaM. Crystal structure, electrophysiology, mutagenesis Structure (London, England : 1993) High 21134641
2013 Apo-state CaBP1 and apo-CaM compete directly for the CaV1 IQ domain, with their relative apo-state binding affinities quantitatively explaining opposing channel regulation; Ca2+/CaM achieves sub-picomolar affinity for the IQ domain; covalent CaM tethering to the channel completely blocks this competition. ITC, cell-based electrophysiology, mathematical modeling, covalent tethering experiments Journal of molecular biology High 23811053
2011 CaBP1 interacts with the distal C-terminal third of the CaV1.2 N-terminal domain in a Ca2+-independent manner (distinct from the calmodulin-binding site), while a separate proximal N-terminal segment is required for transduction of CaBP1's effect on voltage-dependent inactivation (VDI); CaBP1 also causes a depolarizing shift in voltage-dependent activation. Binding assays (pull-down), electrophysiology with deletion mutants The Journal of biological chemistry Medium 21383011
2026 NMR structures of Ca2+-CaBP1 bound to the CaV1.2 IQ peptide identify specific contact residues (CaBP1: A107, F111, M128, L131, I144, M165; IQ: I1654, Y1657, F1658) and a salt bridge (CaBP1-D140 – IQ-K1662); Ca2+ binding to EF3/EF4 enhances IQ-peptide affinity >40-fold; electrophysiology shows CaBP1 increases CaV1.2 channel open probability. NMR structure determination, ITC, electrophysiology, mutagenesis Biochemistry High 41859936
2007 CaBP1 binds the IQ motifs in the myo1c regulatory domain, competing with calmodulin; this competition is enhanced in the presence of Ca2+. CaBP1 has higher apparent affinity for myo1c than CIB1. Both proteins colocalize with myo1c in cells. Pull-down assays, fluorescence microscopy colocalization Journal of muscle research and cell motility Medium 17994197
1994 CaBP1 (rat P5 homolog, ER-resident with KDEL signal) catalyzes renaturation of denatured reduced proteins (Fab fragment, RNase AIII) in a GSH/GSSG redox-dependent manner, showing strong synergism with PDI for RNase AIII refolding, indicating it can catalyze disulfide bond formation and isomerization in the secretory pathway. In vitro renaturation assays with purified protein, activity measurements The Journal of biological chemistry Medium 8300576
1995 CaBP1 (rat ER PDI-family member) is a substrate for thioredoxin reductase, catalyzes NADPH-dependent insulin disulfide reduction, and its thioredoxin active-site disulfide has a redox potential similar to PDI (~−235 mV), much higher than wild-type thioredoxin, consistent with a role in forming protein disulfide bonds. In vitro thioredoxin reductase assay, NADPH stoichiometry, redox potential measurement using P34H Trx mutant equilibrium FEBS letters Medium 7835433
1994 CaBP1 (rat ER PDI-family protein) localizes to the ER lumen (not the intermediate compartment), as demonstrated by subcellular fractionation, double immunofluorescence showing colocalization with calreticulin but not ERGIC-53, and by maintained reticular localization upon overexpression; retention is mediated by the C-terminal KDEL signal. Subcellular fractionation, indirect immunofluorescence, laser scanning microscopy, VSV tsO45 trafficking assay Journal of cell science Medium 7876340
1997 CaBP1 (ER PDI-family) is phosphorylated by protein kinase CK2 at serine 427 (N-terminal site) and at C-terminal serines/threonines by endogenous CK2-type kinase; phosphorylation was also detected in intact hepatocytes. 32P-labeling, purification, proteolytic peptide sequencing, CK2 in vitro kinase assay Journal of biochemistry Medium 9058200
2018 CaBP1 regulates CaV1 (L-type) channels in cochlear spiral ganglion neurons in vivo: CaBP1-knockout SGNs show greater Ca2+-dependent inactivation of CaV1 currents, impaired activity-dependent neurite growth repression unresponsive to CaV1 antagonists, and reduced CaV1-mediated CREB phosphorylation. Whole-cell patch clamp in CaBP1-KO neurons, neurite growth assays, CREB phosphorylation measurements Molecular and cellular neurosciences Medium 29548764
2024 CaBP1 and CaBP2 cooperatively suppress both voltage- and Ca2+-dependent inactivation of IHC CaV1.3 channels; double-KO mice show strongly enhanced inactivation, slowed recovery from inactivation, and impaired sustained exocytosis; transgenic CaBP2 rescue restores IHC synaptic function and hearing. Double-KO mouse electrophysiology (whole-cell patch clamp), exocytosis measurements, in vivo auditory nerve recordings, transgenic rescue eLife High 39718549
2006 L-CaBP1 binds Ca2+-dependently to several partners from bovine brain including ARF1, Ca2+-dependent activator protein for secretion 1, cyclic nucleotide phosphodiesterase, vacuolar ATPase, AP1 and AP2 complexes, and type I TGF-β receptor, with some interactions specific to CaBP1 and not shared with other NCS proteins. GST pull-down from bovine brain cytosol and membrane extracts, MALDI-MS, Western blotting Proteomics Low 16470652

Source papers

Stage 0 corpus · 25 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1994 Effects of CaBP2, the rat analog of ERp72, and of CaBP1 on the refolding of denatured reduced proteins. Comparison with protein disulfide isomerase. The Journal of biological chemistry 77 8300576
2005 Structural analysis of Mg2+ and Ca2+ binding to CaBP1, a neuron-specific regulator of calcium channels. The Journal of biological chemistry 72 16147998
1995 Two resident ER-proteins, CaBP1 and CaBP2, with thioredoxin domains, are substrates for thioredoxin reductase: comparison with protein disulfide isomerase. FEBS letters 72 7835433
2008 Structural insights into Ca2+-dependent regulation of inositol 1,4,5-trisphosphate receptors by CaBP1. The Journal of biological chemistry 52 19008222
2010 Structural basis for the differential effects of CaBP1 and calmodulin on Ca(V)1.2 calcium-dependent inactivation. Structure (London, England : 1993) 51 21134641
2006 Analysis of the interacting partners of the neuronal calcium-binding proteins L-CaBP1, hippocalcin, NCS-1 and neurocalcin delta. Proteomics 50 16470652
2013 Apo states of calmodulin and CaBP1 control CaV1 voltage-gated calcium channel function through direct competition for the IQ domain. Journal of molecular biology 47 23811053
2011 CaBP1 regulates voltage-dependent inactivation and activation of Ca(V)1.2 (L-type) calcium channels. The Journal of biological chemistry 39 21383011
2013 CaBP1, a neuronal Ca2+ sensor protein, inhibits inositol trisphosphate receptors by clamping intersubunit interactions. Proceedings of the National Academy of Sciences of the United States of America 37 23650371
1994 CaBP1, a calcium binding protein of the thioredoxin family, is a resident KDEL protein of the ER and not of the intermediate compartment. Journal of cell science 37 7876340
2014 Localization and expression of CaBP1/caldendrin in the mouse brain. Neuroscience 30 24631676
2021 L-Type Ca2+ Channel Regulation by Calmodulin and CaBP1. Biomolecules 26 34944455
2007 CIB1 and CaBP1 bind to the myo1c regulatory domain. Journal of muscle research and cell motility 25 17994197
1990 The molecular basis for alternative splicing of the CABP1 transcripts in Dictyostelium discoideum. Nucleic acids research 23 2216719
2018 Functions of CaBP1 and CaBP2 in the peripheral auditory system. Hearing research 21 29661613
2016 Lack of CaBP1/Caldendrin or CaBP2 Leads to Altered Ganglion Cell Responses. eNeuro 13 27822497
1997 Phosphorylation of CaBP1 and CaBP2 by protein kinase CK2. Journal of biochemistry 10 9058200
2024 CaBP1 and 2 enable sustained CaV1.3 calcium currents and synaptic transmission in inner hair cells. eLife 7 39718549
2018 CaBP1 regulates Cav1 L-type Ca2+ channels and their coupling to neurite growth and gene transcription in mouse spiral ganglion neurons. Molecular and cellular neurosciences 7 29548764
2008 1H, 15N, and 13C chemical shift assignments of calcium-bound calcium-binding protein 1 (CaBP1). Biomolecular NMR assignments 3 19636926
1998 A homologue of the calcium-binding disulfide isomerase CaBP1 is expressed in the developing CNS of Drosophila melanogaster. Developmental genetics 3 9770267
2007 1H, 15N, and 13C chemical shift assignments of calcium-binding protein 1 (CaBP1). Biomolecular NMR assignments 2 19636832
1991 A 27-bp deletion is responsible for the expression of a variant CABP1, a cyclic AMP-binding protein of Dictyostelium discoideum. Biochimica et biophysica acta 1 1989693
2026 Structural Insights into L-Type Voltage-Gated Ca2+ Channel (CaV1.2) Activation by CaBP1. Biochemistry 0 41859936
2022 Chemical shift assignments of the C-terminal domain of CaBP1 bound to the IQ-motif of voltage-gated Ca2+ channel (CaV1.2). Biomolecular NMR assignments 0 36064846