Structural Insights into Activation of the Retinal L-type Ca2+ Channel (Cav1.4) by Ca2+-binding Protein 4 (CaBP4) [Protein Structure and Folding]

September 25th, 2014 by Park, S., Li, C., Haeseleer, F. J., Palczewski, K., Ames, J. B.

CaBP4 modulates Ca2+-dependent activity of L-type voltage-gated Ca2+ channels (Cav1.4) in retinal photoreceptor cells. Mg2+ binds to the 1st and 3rd EF-hands (EF1 and EF3), and Ca2+ binds to EF1, EF3 and EF4 of CaBP4. Here we present NMR structures of CaBP4 in both Mg2+-bound and Ca2+-bound states and model the CaBP4 structural interaction with Cav1.4. CaBP4 contains an unstructured N-terminal region (residues 1-99) and four EF-hands in two separate lobes. The N-lobe consists of EF1 and EF2 in a closed conformation with either Mg2+ or Ca2+ bound at EF1. The C-lobe binds Ca2+ at EF3 and EF4, and exhibits a Ca2+-induced closed-to-open transition like that of CaM. Exposed residues in Ca2+-bound CaBP4 (F137, E168, L207, F214, M251, F264, L268) make contacts with the IQ-motif in Cav1.4, and the Cav1.4 mutant Y1595E strongly impairs binding to CaBP4. We conclude that CaBP4 forms a collapsed structure around the IQ-motif in Cav1.4 that we suggest may promote channel activation by disrupting an interaction between IQ and ICDI (inhibitor of Ca2+ dependent inactivation).
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