Structural basis for endothelial nitric oxide synthase binding to calmodulin.

The enzyme nitric oxide synthase (NOS) is exquisitely regulated in vivo by the Ca(2+) sensor protein calmodulin (CaM) to control production of NO, a key signaling molecule and cytotoxin. The differential activation of NOS isozymes by CaM has remained enigmatic, despite extensive research. Here, the crystallographic structure of Ca(2+)-loaded CaM ...
bound to a 20 residue peptide comprising the endothelial NOS (eNOS) CaM-binding region establishes their individual conformations and intermolecular interactions, and suggests the basis for isozyme-specific differences. The alpha-helical eNOS peptide binds in an antiparallel orientation to CaM through extensive hydrophobic interactions. Unique NOS interactions occur with: (i). the CaM flexible central linker, explaining its importance in NOS activation; and (ii). the CaM C-terminus, explaining the NOS-specific requirement for a bulky, hydrophobic residue at position 144. This binding mode expands mechanisms for CaM-mediated activation, explains eNOS deactivation by Thr495 phosphorylation, and implicates specific hydrophobic residues in the Ca(2+) independence of inducible NOS.
Mesh Terms:
Amino Acid Sequence, Animals, Binding Sites, Calcium, Calmodulin, Crystallography, X-Ray, Endothelium, Enzyme Activation, Isoenzymes, Molecular Sequence Data, Nitric Oxide Synthase, Nitric Oxide Synthase Type III, Phosphorylation, Protein Binding, Protein Conformation, Rats
EMBO J.
Date: Feb. 17, 2003
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