9zz4 | pdb_00009zz4
NMR structure of CaBP1 bound to the IQ motif of Cav1.2
Structural highlights
FunctionCABP1_HUMAN Modulates calcium-dependent activity of inositol 1,4,5-triphosphate receptors (ITPRs). Inhibits agonist-induced intracellular calcium signaling. Enhances inactivation and does not support calcium-dependent facilitation of voltage-dependent P/Q-type calcium channels. 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 resulting in an opposit effects on channel function. Suppresses the calcium-dependent inactivation of CACNA1D (By similarity). Inhibits TRPC5 channels. Prevents NMDA receptor-induced cellular degeneration (By similarity).[1] [2] [3] [4] [5] Publication Abstract from PubMedThe L-type voltage-gated Ca(2+) channel (Ca(V)1.2) controls gene expression, cardiac function, and neuronal excitability. Mutations in Ca(V)1.2 that disrupt channel function are implicated in cardiac arrhythmias, vascular dysfunction, Timothy Syndrome, and epilepsy. Calcium-binding protein 1 (CaBP1) binds to the IQ-motif in Ca(V)1.2 (residues 1640-1665), blocks Ca(2+)-dependent inactivation (CDI), and promotes Ca(2+)-dependent facilitation (CDF). CaBP1 is 56% identical in sequence to calmodulin (CaM), and both proteins bind competitively to the IQ-motif. Our binding studies reveal that Ca(2+) binding to CaBP1 is enhanced more than 40-fold when CaBP1 is bound to the IQ peptide. Also, the IQ peptide binds to Ca(2+)-bound CaBP1 (dissociation constant of 45 +/- 10 nM) with 100-fold higher affinity than IQ binding to Ca(2+)-free CaBP1. We present NMR structures of Ca(2+)-CaBP1 bound to the IQ peptide, which reveal CaBP1 residues (A107, F111, M128, L131, I144, and M165) that contact IQ residues (I1654, Y1657, and F1658). Also, IQ residue K1662 forms a salt bridge with CaBP1 residue D140, which may explain why a K1662 charge reversal mutation causes 4-fold weaker IQ binding to CaBP1. Electrophysiology studies suggest that CaBP1 acts to increase the Ca(V)1.2 channel open probability (Po). We propose that Ca(2+) binding to the third and fourth EF-hands of CaBP1 and the binding of Ca(2+)-bound CaBP1 to the IQ-motif are important for Ca(V)1.2 channel activation. Structural Insights into L-Type Voltage-Gated Ca(2+) Channel (Ca(V)1.2) Activation by CaBP1.,Salveson I, Anderson DE, Bej A, Nieves-Cintron M, Navedo M, Hell JW, Ames JB Biochemistry. 2026 Mar 20. doi: 10.1021/acs.biochem.6c00032. PMID:41859936[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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