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Structural basis for endothelial nitric oxide synthase binding to calmodulin.

Aoyagi M, Arvai AS, Tainer JA, Getzoff ED
EMBO J 22 766-75 (2003)
Cited: 102 times
EuropePMC logo PMID: 12574113

Abstract

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.

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  1. Use of Computational Biochemistry for Elucidating Molecular Mechanisms of Nitric Oxide Synthase. Bignon E, Rizza S, Filomeni G, Papaleo E. Comput Struct Biotechnol J 17 415-429 (2019)

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