| Budget Amount *help |
¥15,000,000 (Direct Cost: ¥15,000,000)
Fiscal Year 2005: ¥6,500,000 (Direct Cost: ¥6,500,000)
Fiscal Year 2004: ¥8,500,000 (Direct Cost: ¥8,500,000)
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| Research Abstract |
Enzymes called NADPH oxidases produce reactive oxygen species, which play a crucial role in host defense. The catalytic center of the phagocyte NADPH oxidase, the prototype of these enzymes, exists in the membrane protein gp91^<phox>, which is complexed with p22^<phox> to form cytochrome b_<558>. Activation of gp91^<phox> results from stimulus-induced membrane translocation of the specific adaptor proteins p47^<phox>, p67^<phox>, and p40^<phox>, which targeting leads to interaction with the cytochrome. During these two years, we have investigated the mechanism for activation of NADPH oxidases and obtained the following findings.
(1)It is known that the membrane translocation of p47^<phox> requires its interaction with p22^<phox>. We have shown that the interaction is mediated by a novel mode of recognition by the p47^<phox> SH3 domains. In addition, we have determined the NMR structure of the complex of the p47^<phox> SH3 domains with a peptide of p22^<phox>.
(2)The p47^<phox>-p67^<phox>
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interaction is known to be essential for the membrane translocation of p67^<phox>. We have demonstrated that phosphorylation of Ser-379 in p47^<phox> results in attenuation of the p47^<phox>-p67^<phox> interaction, thereby regulating activation of the phagocyte NADPH oxidase.
(3)We have identified the amino acids 151-153 of p47^<phox> as residues that participate in oxidase activation by interacting with gp91^<phox>.
(4)The gp91^<phox> homologue Nox1 is considered to play an important role in host defense by colon epithelial cells. We have revealed that the small GTPase Rac is directly involved in activation of Nox:Rac functions by facilitating membrane localization of Noxa1,a homologue of p67^<phox>, and by inducing a conformational change of Noxa1. We have also shown that Nox3,the gp91^<phox> homologue expressed in the inner ear, forms a heterodimer with p22^<phox>, and Nox3 activity is enhanced by p47^<phox>, Noxo1,or p67^<phox>, the former two of which act by interacting with p22^<phox>. Less
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