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Nat Commun. 2016 Aug 26;7:12673. doi: 10.1038/ncomms12673.

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

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Chemistry Research Laboratory, Department of Chemistry, Oxford Centre for Integrative Systems Biology, University of Oxford, Mansfield Road, Oxford OX1 3TA, UK.
Nuffield Department of Clinical Medicine, University of Oxford, Henry Wellcome Building for Molecular Physiology, Roosevelt Drive, Oxford OX3 7BN, UK.
UMR8576 CNRS-Lille University, Villeneuve d'Ascq 59655, France.
Ludwig Institute for Cancer Research, University of Oxford, Roosevelt Drive, Oxford OX3 7DQ, UK.


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.

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