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In silico phosphorylation of the autoinhibited form of p47(phox): insights into the mechanism of activation.

ABSTRACT: Activation of the multicomponent enzyme NADPH oxidase requires the interaction between the tandem SH3 domain of the cytosolic subunit p47(phox) and the cytoplasmic tail of membrane-bound p22(phox). In the resting state, p47(phox) exists in an autoinhibited conformation stabilized by intramolecular contacts between the SH3 domains and an adjacent polybasic region. Phosphorylation of three serine residues, Ser(303), Ser(304), and Ser(328) within this polybasic region has been shown to be sufficient for the disruption of the intramolecular interactions thereby inducing an active state of p47(phox). This active conformation is accessible to the cytoplasmic tail of p22(phox) and initiates the formation of the membrane-bound functional enzyme complex. Molecular dynamics simulations reveal insights in the mechanism of activation of the autoinhibited form of p47(phox) by in silico phosphorylation, of the three serine residues, Ser(303), Ser(304), and Ser(328). The simulations highlight the major collective coordinates generating the opening and the closing of the two SH3 domains and the residues that cause the unmasking of the p22(phox) binding site.

SUBMITTER: Autore F

PROVIDER: S-EPMC2998635 | biostudies-literature | 2010 Dec

REPOSITORIES: biostudies-literature

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In silico phosphorylation of the autoinhibited form of p47(phox): insights into the mechanism of activation.

Autore Flavia F Pagano Bruno B Fornili Arianna A Rittinger Katrin K Fraternali Franca F

Biophysical journal 20101201 11

Activation of the multicomponent enzyme NADPH oxidase requires the interaction between the tandem SH3 domain of the cytosolic subunit p47(phox) and the cytoplasmic tail of membrane-bound p22(phox). In the resting state, p47(phox) exists in an autoinhibited conformation stabilized by intramolecular contacts between the SH3 domains and an adjacent polybasic region. Phosphorylation of three serine residues, Ser(303), Ser(304), and Ser(328) within this polybasic region has been shown to be sufficien ...[more]

PMID: 21112296

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Project description:BackgroundSpaceflight or microgravity conditions cause myocardial atrophy and dysfunction, contributing to post-flight orthostatic intolerance. However, the underlying mechanisms remain incompletely understood and preventive approaches are limited. This study investigated whether and how losartan, a blocker of angiotensin-II receptor, preserved cardiomyocyte size and prevented myocardial dysfunction during microgravity.MethodAdult male mice were suspended with their tails to simulate microgravity. Echocardiography was performed to assess myocardial function. Heart weight and cardiomyocyte size were measured. NADPH oxidase activation was determined by analyzing membrane translocation of its cytosolic subunits including p47phox, p67phox and Rac1. Heart tissues were also assayed for oxidative stress, p47phox phosphorylation (Ser345), MuRF1 protein levels and angiotensin-II production.ResultsTail-suspension for 28 days increased angiotensin-II production in hearts, decreased cardiomyocyte size and heart weight, and induced myocardial dysfunction. Administration of losartan preserved cardiomyocyte size and heart weight, and prevented myocardial dysfunction in tail-suspended mice. These cardioprotective effects of losartan were associated with inhibition of p47phox phosphorylation (Ser345), NADPH oxidase and oxidative stress in tail-suspended mouse hearts. Additionally, the NADPH oxidase inhibitor, apocynin, also reduced oxidative stress, preserved cardiomyocyte size and heart weight, and improved myocardial function in tail-suspended mice. Furthermore, losartan but not apocynin attenuated tail-suspension-induced up-regulation of MuRF1 protein in mouse hearts.ConclusionsAdministration of losartan preserves cardiomyocyte size and prevents myocardial dysfunction under microgravity by blocking p47phox phosphorylation and NADPH oxidase activation, and by inhibiting MuRF1 expression. Thus, losartan may be a useful drug to prevent microgravity-induced myocardial abnormalities.

Dataset Information

In silico phosphorylation of the autoinhibited form of p47(phox): insights into the mechanism of activation.

Publications

In silico phosphorylation of the autoinhibited form of p47(phox): insights into the mechanism of activation.

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