共查询到20条相似文献,搜索用时 31 毫秒
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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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Recent reports have provided evidence that the β-hydroxylation of conserved asparaginyl residues in ankyrin repeat domain (ARD) proteins is a common posttranslational modification in animal cells. Here, nuclear magnetic resonance (NMR) and other biophysical techniques are used to study the effect of asparaginyl β-hydroxylation on the structure and stability of ‘consensus’ ARD proteins. The NMR analyses support previous work suggesting that a single β-hydroxylation of asparagine can stabilize the stereotypical ARD fold. A second asparaginyl β-hydroxylation causes further stabilization. In combination with mutation studies, the biophysical analyses reveal that the stabilizing effect of β-hydroxylation is, in part, mediated by a hydrogen bond between the asparaginyl β-hydroxyl group and the side chain of a conserved aspartyl residue, two residues to the N-terminal side of the target asparagine. Removal of this hydrogen bond resulted in reduced stabilization by hydroxylation. Formation of the same hydrogen bond is also shown to be a factor in inhibiting binding of hydroxylated ARDs to factor-inhibiting hypoxia-inducible factor (FIH). The effects of hydroxylation appear to be predominantly localized to the target asparagine and proximal residues, at least in the consensus ARD protein. The results reveal that thermodynamic stability is a factor in determining whether a particular ARD protein is an FIH substrate; a consensus ARD protein with three ankyrin repeats is an FIH substrate, while more stable consensus ARD proteins, with four or five ankyrin repeats, are not. However, NMR studies reveal that the consensus protein with four ankyrin repeats is still able to bind to FIH, suggesting that FIH may interact in cells with natural ankyrin repeats without resulting hydroxylation. Overall, the work provides novel biophysical insights into the mechanism by which asparaginyl β-hydroxylation stabilizes the ARD proteins and reduces their binding to FIH. 相似文献
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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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Hypoxia-inducible factor (HIF) asparagine hydroxylase is identical to factor inhibiting HIF (FIH) and is related to the cupin structural family 总被引:14,自引:0,他引:14
Hewitson KS McNeill LA Riordan MV Tian YM Bullock AN Welford RW Elkins JM Oldham NJ Bhattacharya S Gleadle JM Ratcliffe PJ Pugh CW Schofield CJ 《The Journal of biological chemistry》2002,277(29):26351-26355
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Thomas M. Leissing Adam P. Hardy Hokfung Chan Yihua Wang Anthony Tumber Rasheduzzaman Chowdhury Tianshu Feng Mathew L. Coleman Matthew E. Cockman Holger B. Kramer Georgina Berridge Roman Fischer Benedikt M. Kessler Peter J. Ratcliffe Xin Lu Christopher J. Schofield 《The Journal of biological chemistry》2022,298(6)
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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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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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缺氧诱导因子(hypoxia-inducible factor, HIF)是异二聚体的转录因子,由氧敏感的α亚基和在细胞内稳定表达的β亚基组成,在细胞缺氧应答反应中起核心作用.缺氧诱导因子脯氨酰羟化酶(prolyl hydroxylase domain-containing proteins, PHDs)和天冬酰胺酰羟化酶,即缺氧诱导因子抑制因子(factor-inhibiting HIF, FIH)是调节缺氧诱导因子蛋白质水平和活性的2类关键酶,它们自身的催化活性受细胞内氧张力的调节,因而被称为细胞氧感受器.目前,大多数的研究都集中于PHDs,而对FIH的研究相对较少.本文主要就FIH的发现、晶体结构、生物学特征以及表达水平和活性调节等方面作一综述. 相似文献
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HIF hydroxylation and cellular oxygen sensing 总被引:7,自引:0,他引:7
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