9ZZ4

NMR structure of CaBP1 bound to the IQ motif of Cav1.2

Summary for 9ZZ4

• Entry DOI: 10.2210/pdb9zz4/pdb
• NMR Information: BMRB: 51518
• Descriptor: Calcium-binding protein 1, Voltage-dependent L-type calcium channel subunit alpha-1C, CALCIUM ION (3 entities in total)
• Functional Keywords: metal binding protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 20823.66

Authors

Salveson, I.,Anderson, D.E.,Bej, A.,Ames, J.B. (deposition date: 2026-01-06, release date: 2026-04-08, Last modification date: 2026-05-27)

Primary citation

Salveson, I.,Anderson, D.E.,Bej, A.,Nieves-Cintron, M.,Navedo, M.,Hell, J.W.,Ames, J.B.
Structural Insights into L-Type Voltage-Gated Ca 2+ Channel (Ca V 1.2) Activation by CaBP1.
Biochemistry, 65:1668-1676, 2026

PubMed Abstract: The L-type voltage-gated Ca channel (Ca1.2) controls gene expression, cardiac function, and neuronal excitability. Mutations in Ca1.2 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 Ca1.2 (residues 1640-1665), blocks Ca-dependent inactivation (CDI), and promotes Ca-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 binding to CaBP1 is enhanced more than 40-fold when CaBP1 is bound to the IQ peptide. Also, the IQ peptide binds to Ca-bound CaBP1 (dissociation constant of 45 ± 10 nM) with 100-fold higher affinity than IQ binding to Ca-free CaBP1. We present NMR structures of Ca-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 Ca1.2 channel open probability (Po). We propose that Ca binding to the third and fourth EF-hands of CaBP1 and the binding of Ca-bound CaBP1 to the IQ-motif are important for Ca1.2 channel activation.

PubMed: 41859936
DOI: 10.1021/acs.biochem.6c00032

Experimental method

SOLUTION NMR