Structural basis for the differential effects of CaBP1 and calmodulin on Ca(V)1.2 calcium-dependent inactivation

Structure. 2010 Dec 8;18(12):1617-31. doi: 10.1016/j.str.2010.09.012.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Binding Sites
  • Calcium / metabolism
  • Calcium / pharmacology*
  • Calcium Channels, L-Type / chemistry*
  • Calcium Channels, L-Type / drug effects*
  • Calcium Channels, L-Type / metabolism
  • Calcium-Binding Proteins / chemistry
  • Calcium-Binding Proteins / metabolism
  • Calcium-Binding Proteins / pharmacology*
  • Calmodulin / chemistry
  • Calmodulin / metabolism
  • Calmodulin / pharmacology*
  • Crystallography, X-Ray
  • Humans
  • Ion Channel Gating / drug effects*
  • Models, Biological
  • Models, Molecular
  • Molecular Sequence Data
  • Protein Structure, Secondary
  • Protein Structure, Tertiary
  • Sequence Homology, Amino Acid


  • Calcium Channels, L-Type
  • Calcium-Binding Proteins
  • Calmodulin
  • L-type calcium channel alpha(1C)
  • Ca2+-binding protein-1
  • Calcium