Structural basis for the differential effects of CaBP1 and calmodulin on Ca(V)1.2 calcium-dependent inactivation.
Calcium-binding protein 1 (CaBP1), a calmodulin (CaM) homolog, endows certain voltage-gated calcium channels (Ca(V)s) with unusual properties. CaBP1 inhibits Ca(V)1.2 calcium-dependent inactivation (CDI) and introduces calcium-dependent facilitation (CDF). Here, we show that the ability of CaBP1 to inhibit Ca(V)1.2 CDI and induce CDF arises from interaction between the CaBP1 N-lobe and interlobe linker residue Glu94. Unlike CaM, where functional EF hands are essential for channel modulation, CDI inhibition does not require functional CaBP1 EF hands. Furthermore, CaBP1-mediated CDF has different molecular requirements than CaM-mediated CDF. Overall, the data show that CaBP1 comprises two structural modules having separate functions: similar to CaM, the CaBP1 C-lobe serves as a high-affinity anchor that binds the Ca(V)1.2 IQ domain at a site that overlaps with the Ca²+/CaM C-lobe site, whereas the N-lobe/linker module houses the elements required for channel modulation. Discovery of this division provides the framework for understanding how CaBP1 regulates Ca(V)s.
Cardiovascular Research Institute, University of California, San Francisco, CA 94158-2330, USA.
Felix
F
Findeisen
Daniel L
DL
Minor
D000595:Amino Acid Sequence; D001665:Binding Sites; D002118:Calcium / Q000378:metabolism / Q000494:pharmacology*; D020746:Calcium Channels, L-Type / Q000737:chemistry* / Q000187:drug effects* / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D002147:Calmodulin / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects*; D008954:Models, Biological; D008958:Models, Molecular; D008969:Molecular Sequence Data; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid
D020746:Calcium Channels, L-Type; D002135:Calcium-Binding Proteins; D002147:Calmodulin; C419385:L-type calcium channel alpha(1C); C085577:Ca2+-binding protein-1; D002118:Calcium