| First Author | Aoyagi M | Year | 2003 |
| Journal | EMBO J | Volume | 22 |
| Issue | 4 | Pages | 766-75 |
| PubMed ID | 12574113 | Mgi Jnum | J:81912 |
| Mgi Id | MGI:2450219 | Doi | 10.1093/emboj/cdg078 |
| Citation | Aoyagi M, et al. (2003) Structural basis for endothelial nitric oxide synthase binding to calmodulin. EMBO J 22(4):766-75 |
| abstractText | 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 crystal lographic 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. |
