Publication

Article Metrics

Citations


Online attention

Structural basis for oxygen degradation domain selectivity of the HIF prolyl hydroxylases

DOI: 10.1038/ncomms12673 DOI Help

Authors: Rasheduzzaman Chowdhury (Department of Chemistry, University of Oxford) , Ivanhoe K. H. Leung (Chemistry Research Laboratory, Department of Chemistry, Oxford Centre for Integrative Systems Biology, University of Oxford) , Ya-min Tian (Nuffield Department of Clinical Medicine, University of Oxford) , Martine I. Abboud (Chemistry Research Laboratory, Department of Chemistry, Oxford Centre for Integrative Systems Biology, University of Oxford) , Wei Ge (Chemistry Research Laboratory, Department of Chemistry, Oxford Centre for Integrative Systems Biology, University of Oxford) , Carmen Domene (Chemistry Research Laboratory, Department of Chemistry, Oxford Centre for Integrative Systems Biology, University of Oxford) , François-xavier Cantrelle (UMR8576 CNRS-Lille University) , Isabelle Landrieu (UMR8576 CNRS-Lille University) , Adam P. Hardy (Chemistry Research Laboratory, Department of Chemistry, Oxford Centre for Integrative Systems Biology, University of Oxford) , Christopher W. Pugh (Nuffield Department of Clinical Medicine, University of Oxford) , Peter J. Ratcliffe (Nuffield Department of Clinical Medicine, University of Oxford) , Timothy D. W. Claridge (Chemistry Research Laboratory, Department of Chemistry, Oxford Centre for Integrative Systems Biology, University of Oxford) , Christopher J. Schofield (Chemistry Research Laboratory, Department of Chemistry, Oxford Centre for Integrative Systems Biology, University of Oxford)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nature Communications , VOL 7

State: Published (Approved)
Published: August 2016
Diamond Proposal Number(s): 12346

Open Access Open Access

Abstract: The response to hypoxia in animals involves the expression of multiple genes regulated by the αβ-hypoxia-inducible transcription factors (HIFs). The hypoxia-sensing mechanism involves oxygen limited hydroxylation of prolyl residues in the N- and C-terminal oxygen-dependent degradation domains (NODD and CODD) of HIFα isoforms, as catalysed by prolyl hydroxylases (PHD 1–3). Prolyl hydroxylation promotes binding of HIFα to the von Hippel–Lindau protein (VHL)–elongin B/C complex, thus signalling for proteosomal degradation of HIFα. We reveal that certain PHD2 variants linked to familial erythrocytosis and cancer are highly selective for CODD or NODD. Crystalline and solution state studies coupled to kinetic and cellular analyses reveal how wild-type and variant PHDs achieve ODD selectivity via different dynamic interactions involving loop and C-terminal regions. The results inform on how HIF target gene selectivity is achieved and will be of use in developing selective PHD inhibitors.

Journal Keywords: Chemical modification; Enzyme mechanisms; Structural biology

Subject Areas: Medicine


Instruments: I02-Macromolecular Crystallography , I03-Macromolecular Crystallography , I04-1-Macromolecular Crystallography (fixed wavelength) , I04-Macromolecular Crystallography

Documents:
ncomms12673.pdf

Discipline Tags:



Technical Tags: