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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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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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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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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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Gelse K Pfander D Obier S Knaup KX Wiesener M Hennig FF Swoboda B 《Arthritis research & therapy》2008,10(5):R111
Introduction
Chondrocytes have to withstand considerable hypoxic conditions within the avascular articular cartilage. The present study investigated the effects of inhibiting or stabilizing hypoxia-inducible factor (HIF)-1α by 2-methoxyestradiol or dimethyloxaloylglycine on the progression of osteoarthritis in murine knee joints. 相似文献18.
Background
Ranaviruses (family Iridoviridae) are important pathogens of lower vertebrates. However, little is known about how they circumvent the immune response of their hosts. Many ranaviruses contain a predicted protein, designated vIF2α, which shows homology with the eukaryotic translation initiation factor 2α. In analogy to distantly related proteins found in poxviruses vIF2α might act as an inhibitor of the antiviral protein kinase PKR. 相似文献19.
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