共查询到20条相似文献,搜索用时 15 毫秒
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Stolze IP Tian YM Appelhoff RJ Turley H Wykoff CC Gleadle JM Ratcliffe PJ 《The Journal of biological chemistry》2004,279(41):42719-42725
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HIF hydroxylation and cellular oxygen sensing 总被引:7,自引:0,他引:7
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Yang M Chowdhury R Ge W Hamed RB McDonough MA Claridge TD Kessler BM Cockman ME Ratcliffe PJ Schofield CJ 《The FEBS journal》2011,278(7):1086-1097
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Hewitson KS Holmes SL Ehrismann D Hardy AP Chowdhury R Schofield CJ McDonough MA 《The Journal of biological chemistry》2008,283(38):25971-25978
A 2-His-1-carboxylate triad of iron binding residues is present in many non-heme iron oxygenases including the Fe(II) and 2-oxoglutarate (2OG)-dependent dioxygenases. Three variants (D201A, D201E, and D201G) of the iron binding Asp-201 residue of an asparaginyl hydroxylase, factor inhibiting HIF (FIH), were made and analyzed. FIH-D201A and FIH-D201E did not catalyze asparaginyl hydroxylation, but in the presence of a reducing agent, they displayed enhanced 2OG turnover when compared with wild-type FIH. Turnover of 2OG by FIH-D201A was significantly stimulated by the addition of HIF-1alpha(786-826) peptide. Like FIH-D201A and D201E, the D201G variant enhanced 2OG turnover but rather unexpectedly catalyzed asparaginyl hydroxylation. Crystal structures of the FIH-D201A and D201G variants in complex with Fe(II)/Zn(II), 2OG, and HIF-1alpha(786-826/788-806) implied that only two FIH-based residues (His-199 and His-279) are required for metal binding. The results indicate that variation of 2OG-dependent dioxygenase iron-ligating residues as a means of functional assignment should be treated with caution. The results are of mechanistic interest in the light of recent biochemical and structural analyses of non-heme iron and 2OG-dependent halogenases that are similar to the FIH-D201A/G variants in that they use only two His-residues to ligate iron. 相似文献
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Asparaginyl hydroxylation of the Notch ankyrin repeat domain by factor inhibiting hypoxia-inducible factor 总被引:2,自引:0,他引:2
Coleman ML McDonough MA Hewitson KS Coles C Mecinovic J Edelmann M Cook KM Cockman ME Lancaster DE Kessler BM Oldham NJ Ratcliffe PJ Schofield CJ 《The Journal of biological chemistry》2007,282(33):24027-24038
The stability and activity of hypoxia-inducible factor (HIF) are regulated by the post-translational hydroxylation of specific prolyl and asparaginyl residues. We show that the HIF asparaginyl hydroxylase, factor inhibiting HIF (FIH), also catalyzes hydroxylation of highly conserved asparaginyl residues within ankyrin repeat (AR) domains (ARDs) of endogenous Notch receptors. AR hydroxylation decreases the extent of ARD binding to FIH while not affecting signaling through the canonical Notch pathway. ARD proteins were found to efficiently compete with HIF for FIH-dependent hydroxylation. Crystallographic analyses of the hydroxylated Notch ARD (2.35A) and of Notch peptides bound to FIH (2.4-2.6A) reveal the stereochemistry of hydroxylation on the AR and imply that significant conformational changes are required in the ARD fold in order to enable hydroxylation at the FIH active site. We propose that ARD proteins function as natural inhibitors of FIH and that the hydroxylation status of these proteins provides another oxygen-dependent interface that modulates HIF signaling. 相似文献
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Cockman ME Webb JD Kramer HB Kessler BM Ratcliffe PJ 《Molecular & cellular proteomics : MCP》2009,8(3):535-546
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The use of dioxygen by HIF prolyl hydroxylase (PHD1) 总被引:9,自引:0,他引:9
McNeill LA Hewitson KS Gleadle JM Horsfall LE Oldham NJ Maxwell PH Pugh CW Ratcliffe PJ Schofield CJ 《Bioorganic & medicinal chemistry letters》2002,12(12):1547-1550
The hypoxic response in animals is mediated by hydroxylation of proline residues in the alpha-subunit of hypoxia inducible factor (HIF). Hydroxylation is catalysed by prolyl-4-hydroxylases (PHD isozymes in humans) which are iron(II) and 2-oxoglutarate dependent oxygenases. Mutation of the arginine proposed to bind 2-oxoglutarate and of the 2His-1-carboxylate iron(II) binding motif in PHD1 dramatically reduces its activity. The source of the oxygen of the product alcohol is (>95%) dioxygen. 相似文献