title: Molecular dynamics study on the ligand recognition by tandem SH3 domains of p47phox, regulating NADPH oxidase activity.
abstract: The phagocyte NADPH oxidase complex plays a crucial role in host defense against microbial infection through the production of superoxides. Chronic granulomatous disease (CGD) is an inherited immune deficiency caused by the absence of certain components of the NADPH oxidase. Key to the activation of the NADPH oxidase is the cytoplasmic subunit p47phox, which includes the tandem SH3 domains (N-SH3 and C-SH3). In active phagocytes, p47phox forms a stable complex with the cytoplasmic region of membrane subunit p22phox that forms a left-handed polyproline type-II (PPII) helix conformation. In this report, we have analyzed the conformational changes of p47phox-p22phox complexes of wild-type and three mutants, which have been detected in CGD patients, using molecular dynamics simulations. We have found that in the wild-type, two basal planes of PPII prism in cytoplasmic region of p22phox interacted with N-SH3 and C-SH3. In contrast, in the modeled mutants, the residue at the ape of PPII helix, which interacts simultaneously with both of the tandem SH3 domains in the wild-type, moved toward C-SH3. Furthermore, interaction energies of the cytoplasmic region of p22phox with C-SH3 tend to decrease in these mutants. All these findings led us to conclude that interactions between N-SH3 of p47phox and PPII helix, which is formed by cytoplasmic region of p22phox, may play a significant role in the activation of the NADPH oxidase.
authors.affiliation: Department of Applied Chemistry, Graduate School of Engineering, Tohoku University, 6-6-11-1302 Aoba, Aramaki, Aoba-ku, Sendai 980-8579, Japan.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Watanabe
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Tsuboi
authors.forename: Michihisa
authors.initials: M
authors.lastname: Koyama
authors.forename: Momoji
authors.initials: M
authors.lastname: Kubo
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Del Carpio
authors.forename: Ewa
authors.initials: E
authors.lastname: Broclawik
authors.forename: Eiichiro
authors.initials: E
authors.lastname: Ichiishi
authors.forename: Masahiro
authors.initials: M
authors.lastname: Kohno
authors.forename: Akira
authors.initials: A
authors.lastname: Miyamoto
mesh_terms: D019295:Computational Biology; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D004789:Enzyme Activation; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D019255:NADPH Oxidases / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D013997:Time Factors; D018909:src Homology Domains
chemical_list: D008024:Ligands; D019255:NADPH Oxidases; C086986:CYBA protein, human; C060505:neutrophil cytosolic factor 1