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Structural basis for isozyme-specific regulation of electron transfer in nitric-oxide synthase
E D GARCIN, C M BRUNS, S J LLOYD, D J HOSFIELD, M TISO, R GACHHUI, D J STUEHR, J A TAINER, E D GETZOFF
Published in -
2004
Volume: 279
   
Issue: 36
Pages: 37918 - 37927
Abstract
Three nitric-oxide synthase (NOS) isozymes play crucial, but distinct, roles in neurotransmission, vascular homeostasis, and host defense, by catalyzing Ca2+/calmodulim-triggered NO synthesis. Here, we address current questions regarding NOS activity and regulation by combining mutagenesis and biochemistry with crystal structure determination of a fully assembled, electron-supplying, neuronal NOS reductase dimer. By integrating these results, we structurally elucidate the unique mechanisms for isozyme-specific regulation of electron transfer in NOS. Our discovery of the autoinhibitory helix, its placement between domains, and striking similarities with canonical calmodulin-binding motifs, support new mechanisms for NOS inhibition. NADPH, isozyme-specifie residue Arg1400, and the C-terminal tail synergistically repress NOS activity by locking the FMN binding domain in an electron-accepting position. Our analyses suggest that calmodulin binding or C-terminal tail phosphorylation frees a large scale swinging motion of the entire FMN domain to deliver electrons to the catalytic module in the holoenzyme.
About the journal
JournalJournal of Biological Chemistry
Publisher-
ISSN0021-9258
Open AccessYes