Calmodulin-induced Conformational Control and Allostery Underlying Neuronal Nitric Oxide Synthase Activation. J Mol Biol 2018 Mar 30;430(7):935-947
Date
02/20/2018Pubmed ID
29458127DOI
10.1016/j.jmb.2018.02.003Scopus ID
2-s2.0-85042563266 (requires institutional sign-in at Scopus site) 15 CitationsAbstract
Nitric oxide synthase (NOS) is the primary generator of nitric oxide signals controlling diverse physiological processes such as neurotransmission and vasodilation. NOS activation is contingent on Ca2+/calmodulin binding at a linker between its oxygenase and reductase domains to induce large conformational changes that orchestrate inter-domain electron transfer. However, the structural dynamics underlying activation of full-length NOS remain ambiguous. Employing hydrogen-deuterium exchange mass spectrometry, we reveal mechanisms underlying neuronal NOS activation by calmodulin and regulation by phosphorylation. We demonstrate that calmodulin binding orders the junction between reductase and oxygenase domains, exposes the FMN subdomain, and elicits a more dynamic oxygenase active site. Furthermore, we demonstrate that phosphorylation partially mimics calmodulin activation to modulate neuronal NOS activity via long-range allostery. Calmodulin binding and phosphorylation ultimately promote a more dynamic holoenzyme while coordinating inter-domain communication and electron transfer.
Author List
Hanson QM, Carley JR, Gilbreath TJ, Smith BC, Underbakke ESAuthor
Brian C. Smith PhD Associate Professor in the Biochemistry department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Allosteric RegulationCalmodulin
Catalytic Domain
Deuterium Exchange Measurement
Enzyme Activation
Humans
Nitric Oxide Synthase Type I
Protein Conformation