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Patrick R. Arsenault Katherine J. Heaton‐Johnson Lin‐sheng Li Daisheng Song Vinicius S. Ferreira Nish Patel Frank S. Lee 《Proteomics》2015,15(7):1259-1267
Prolyl hydroxylation is a PTM that plays an important role in the formation of collagen fibrils and in the oxygen‐dependent regulation of hypoxia inducible factor‐α (HIF‐α). While this modification has been well characterized in the context of these proteins, it remains unclear to what extent it occurs in the remaining mammalian proteome. We explored this question using MS to analyze cellular extracts subjected to various fractionation strategies. In one strategy, we employed the von Hippel Lindau tumor suppressor protein, which recognizes prolyl hydroxylated HIF‐α, as a scaffold for generating hydroxyproline capture reagents. We report novel sites of prolyl hydroxylation within five proteins: FK506‐binding protein 10, myosin heavy chain 10, hexokinase 2, pyruvate kinase, and C‐1 Tetrahydrofolate synthase. Furthermore, we show that identification of prolyl hydroxylation presents a significant technical challenge owing to widespread isobaric methionine oxidation, and that manual inspection of spectra of modified peptides in this context is critical for validation. 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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The von Hippel-Lindau tumor suppressor protein: new insights into oxygen sensing and cancer 总被引:18,自引:0,他引:18
The von Hippel-Lindau tumor suppressor protein (pVHL) is the substrate-recognition module of an E3 ubiquitin ligase that targets the alpha subunits of hypoxia-inducible factor (HIF) for degradation in the presence of oxygen. Recognition of HIF by pVHL is linked to enzymatic hydroxylation of conserved prolyl residues in the HIF alpha subunits by members of the EGLN family. Dysregulation of HIF-target genes such as vascular endothelial growth factor and transforming growth factor alpha has been implicated in the pathogenesis of renal cell carcinomas and of hemangioblastomas, both of which frequently lack pVHL function. 相似文献
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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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Gabriel Limaverde‐Sousa Ester de Andrade Barreto Carlos Gil Ferreira José Cláudio Casali‐da‐Rocha 《Proteins》2013,81(2):349-363
The von Hippel–Lindau tumor suppressor protein (pVHL) plays a central role in the oxygen‐sensing pathway by regulating the degradation of the hypoxia‐inducible factor (HIF‐1α). The capture of HIF‐1α by pVHL is regulated by an oxygen‐dependent hydroxylation of a specific conserved prolyl residue. The VHL gene is mutated in the von Hippel–Lindau cancer predisposition syndrome, which is characterized by the development of highly vascularized tumors and is associated with constitutively high levels of HIF‐1α. The disturbance of the dynamic coupling between HIF‐1α and pVHL bearing the commonly found mutation F76del was experimentally confirmed but the mechanism of such complex disruption is still not clear. Performing unbiased molecular dynamics simulations, we show that the F76del mutation may enlarge the HIF binding pocket in pVHL and induce the formation of an internal cavity in the hydrophobic core of the β‐domain, which can lead to a partial destabilization of the β‐sheets S1, S4, and S7 and a consequent loss of hydrogen bonds with a conserved recognition motif in HIF. The newly formed cavity has a significant druggability score and may be a suitable target for stabilizing ligands. Studies of this nature may help to fill the information gap between genotype–phenotype correlations with details obtained at atomic level and provide basis for future development of drug candidates, such as pharmacological chaperones, with the specific aim of reverting the dysfunction of such pathological protein complexes found in patients with VHL. Proteins 2013. © 2012 Wiley Periodicals, Inc. 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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The peptidyl prolyl cis/trans isomerase FKBP38 determines hypoxia-inducible transcription factor prolyl-4-hydroxylase PHD2 protein stability
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Barth S Nesper J Hasgall PA Wirthner R Nytko KJ Edlich F Katschinski DM Stiehl DP Wenger RH Camenisch G 《Molecular and cellular biology》2007,27(10):3758-3768