The DOI matches its Crossref record; 34 of the 34 references it cites were found in a registry or an index.
Asparaginyl Hydroxylation of the Notch Ankyrin Repeat Domain by Factor Inhibiting Hypoxia-inducible Factor
Open accessAbstract
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.
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“It also seems that increased NF-κB activity in hypoxia can be regulated by HIF-144, thus a cross-regulatory loop may exist between these two pathways and may involve other transcriptional regulators that bear non-redundant PHD sensitivity, including activating transcription factor-4 and Notch52,53”
From Hypoxia: an alarm signal during intestinal inflammation (2010) · cites this paper as [52]
Citations
Cites
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Self-citationHypoxia requires Notch signaling to maintain the undifferentiated cell state
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Self-citationActivation of Hypoxia-inducible Factor-1; Definition of Regulatory Domains within the α Subunit
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A protein hydroxylase couples epithelial membrane biology to nucleolar ribosome biogenesisPreprint
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Self-citationCellular and functional insights into FIH-mediated hydroxylation of TRPA1
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Self-citationProbing the druggability of the Notch1 ankyrin domain using a fragment-based approach
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The Dual Role of HIF Hydroxylase PHD3 in Cancer Cell Survival
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Metadata
- Authors
- Coleman, M. L., McDonough, M. A., Hewitson, K. S., Coles, C., Mecinovicí, J., Edelmann, M., Cook, K. M., Cockman, M. E., Lancaster, D. E., Kessler, B. M., Oldham, N. J., Ratcliffe, P. J., & Schofield, C. J.
- Affiliations
- University of Oxford (GB)
- Corresponding author
- Schofield, Christopher J.
- ORCID
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2007-08
- Volume
- 282
- Issue
- 33
- Pages
- 24027-24038
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2078263362
- Cited by
- 222
- References
- 34
- Citations by year
- 2026: 1 · 2025: 7 · 2024: 4 · 2023: 7 · 2022: 9 · 2021: 5 · 2020: 8 · 2019: 10 · 2018: 7 · 2017: 8 · 2016: 10 · 2015: 13 · 2014: 14 · 2013: 19 · 2012: 11
- FWCI
- 8.31
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- University of Birmingham Research Portal (University of Birmingham) (submittedVersion)
- Funders
- Wellcome Trust
- Biotechnology and Biological Sciences Research Council (BBS/B/07683)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Physical Sciences › Chemistry › Inorganic Chemistry › Metal-Catalyzed Oxygenation Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Keywords
- FIH, Notch receptor, ankyrin repeat domain, hypoxia-inducible factor, protein stability, oxygen sensing, protein-protein interaction, conformational change, crystal structure, Notch signaling
- MeSH terms
- Receptor, Notch3, Asparagine, Humans, Mixed Function Oxygenases, Hydroxylation, Repressor Proteins, Transcription Factors, Ankyrin Repeat, Protein Structure, Tertiary, Crystallography, X-Ray, Hypoxia-Inducible Factor 1, alpha Subunit, Receptors, Notch, Receptor, Notch1, Receptor, Notch2
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