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- Title
Structural basis for endothelial nitric oxide synthase binding to calmodulin.
- Authors
Aoyagi, Mika; Arvai, Andrew S.; Tainer, John A.; Getzoff, Elizabeth D.
- Abstract
The enzyme nitric oxide synthase (NOS) is exquisitely regulated in vivo by the Ca2+ 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 Ca2+-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 α-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 Ca2+ independence of inducible NOS.
- Subjects
NITRIC oxide; CALMODULIN; CALCIUM ions; ENZYMES; RESEARCH; HYDROPHOBIC surfaces; PEPTIDES
- Publication
EMBO Journal, 2003, Vol 22, Issue 4, p766
- ISSN
0261-4189
- Publication type
Article
- DOI
10.1093/emboj/cdg078