Importance of the domain-domain interface to the catalytic action of the NO synthase reductase domain

Biochemistry
Andrew WellandS Daff

Abstract

Calmodulin (CaM) activates NO synthase (NOS) by binding to a 20 amino acid interdomain hinge in the presence of Ca (2+), inducing electrons to be transferred from the FAD to the heme of the enzyme via a mobile FMN domain. The activation process is influenced by a number of structural features, including an autoinhibitory loop, the C-terminal tail of the enzyme, and a number of phosphorylation sites. Crystallographic and other recent experimental data imply that the regulatory elements lie within the interface between the FAD- and FMN-binding domains, restricting the movement of the two cofactors with respect to each other. Arg1229 of rat neuronal NOS is a conserved residue in the FAD domain that forms one of only two electrostatic contacts between the domains. Mutation of this residue to Glu reverses its charge and is expected to induce an interdomain repulsion, allowing the importance of the interface and domain-domain motion to be probed. The charge-reversal mutation R1229E has three dramatic effects on catalysis: (i) hydride transfer from NADPH to FAD is activated in the CaM-free enzyme, (ii) FAD to FMN electron transfer is inhibited in both forms, and (iii) electron transfer from FMN to the surrogate acceptor cytochrome c i...Continue Reading

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Citations

Mar 13, 2012·Journal of Biological Inorganic Chemistry : JBIC : a Publication of the Society of Biological Inorganic Chemistry·Wenbing LiChangjian Feng
Mar 18, 2009·Biochemistry·Robielyn P IlaganDennis J Stuehr
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Oct 30, 2016·The Journal of Biological Chemistry·Mohammad Mahfuzul HaqueDennis J Stuehr

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