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

Rasheduzzaman Chowdhury, Ivanhoe K. H. Leung, Ya-Min Tian, Martine I. Abboud, Wei Ge, Carmen Domene, François-Xavier Cantrelle, Isabelle Landrieu, Adam P. Hardy, Christopher W. Pugh, Peter J. Ratcliffe, Timothy D. W. Claridge and Christopher J. Schofield ()
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Rasheduzzaman Chowdhury: Chemistry Research Laboratory, Oxford Centre for Integrative Systems Biology, University of Oxford
Ivanhoe K. H. Leung: Chemistry Research Laboratory, Oxford Centre for Integrative Systems Biology, University of Oxford
Ya-Min Tian: University of Oxford
Martine I. Abboud: Chemistry Research Laboratory, Oxford Centre for Integrative Systems Biology, University of Oxford
Wei Ge: Chemistry Research Laboratory, Oxford Centre for Integrative Systems Biology, University of Oxford
Carmen Domene: Chemistry Research Laboratory, 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, Oxford Centre for Integrative Systems Biology, University of Oxford
Christopher W. Pugh: University of Oxford
Peter J. Ratcliffe: University of Oxford
Timothy D. W. Claridge: Chemistry Research Laboratory, Oxford Centre for Integrative Systems Biology, University of Oxford
Christopher J. Schofield: Chemistry Research Laboratory, Oxford Centre for Integrative Systems Biology, University of Oxford

Nature Communications, 2016, vol. 7, issue 1, 1-10

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms12673

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