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 polybastc 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
In silico phosphorylation of the autoinhibited form of p47(phox): Insights into the mechanism of activation / Autore, F.; Pagano, Bruno; Fornili, A.; Rittinger, K.; Fraternali, F.. - In: BIOPHYSICAL JOURNAL. - ISSN 0006-3495. - STAMPA. - 99:11(2010), pp. 3716-3725. [10.1016/j.bpj.2010.09.008]
In silico phosphorylation of the autoinhibited form of p47(phox): Insights into the mechanism of activation
PAGANO, BRUNO;
2010
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 polybastc 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 siteI documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
