Structural insights into Ca2+-dependent regulation of inositol 1,4,5-trisphosphate receptors by CaBP1.
Calcium-binding protein 1 (CaBP1), a neuron-specific member of the calmodulin (CaM) superfamily, modulates Ca2+-dependent activity of inositol 1,4,5-trisphosphate receptors (InsP3Rs). Here we present NMR structures of CaBP1 in both Mg2+-bound and Ca2+-bound states and their structural interaction with InsP3Rs. CaBP1 contains four EF-hands in two separate domains. The N-domain consists of EF1 and EF2 in a closed conformation with Mg2+ bound at EF1. The C-domain binds Ca2+ at EF3 and EF4, and exhibits a Ca2+-induced closed to open transition like that of CaM. The Ca2+-bound C-domain contains exposed hydrophobic residues (Leu132, His134, Ile141, Ile144, and Val148) that may account for selective binding to InsP3Rs. Isothermal titration calorimetry analysis reveals a Ca2+-induced binding of the CaBP1 C-domain to the N-terminal region of InsP3R (residues 1-587), whereas CaM and the CaBP1 N-domain did not show appreciable binding. CaBP1 binding to InsP3Rs requires both the suppressor and ligand-binding core domains, but has no effect on InsP3 binding to the receptor. We propose that CaBP1 may regulate Ca2+-dependent activity of InsP3Rs by promoting structural contacts between the suppressor and core domains.
Li
Congmin
C
Department of Chemistry, University of California, Davis, California 95616, USA.
Chan
Jenny
J
Haeseleer
Franciose
F
Mikoshiba
Katsuhiko
K
Palczewski
Krzysztof
K
Ikura
Mitsuhiko
M
Ames
James B
JB
D000595:Amino Acid Sequence; D002118:Calcium / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002147:Calmodulin / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D020832:EF Hand Motifs; D006801:Humans; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000378:metabolism*; D008274:Magnesium / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D019906:Nuclear Magnetic Resonance, Biomolecular; D055503:Protein Multimerization; D020836:Protein Structure, Quaternary; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment
D002135:Calcium-Binding Proteins; D002147:Calmodulin; D053496:Inositol 1,4,5-Trisphosphate Receptors; C085577:Ca2+-binding protein-1; D008274:Magnesium; D002118:Calcium