title: Structural basis for oxygen degradation domain selectivity of the HIF prolyl hydroxylases.
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.
authors: Chemistry Research Laboratory, Department of Chemistry, Oxford Centre for Integrative Systems Biology, University of Oxford, Mansfield Road, Oxford OX1 3TA, UK.
authors: Rasheduzzaman
authors: R
authors: Chowdhury
authors: Chemistry Research Laboratory, Department of Chemistry, Oxford Centre for Integrative Systems Biology, University of Oxford, Mansfield Road, Oxford OX1 3TA, UK.
authors: Ivanhoe K H
authors: IK
authors: Leung
authors: Nuffield Department of Clinical Medicine, University of Oxford, Henry Wellcome Building for Molecular Physiology, Roosevelt Drive, Oxford OX3 7BN, UK.
authors: Ya-Min
authors: YM
authors: Tian
authors: Chemistry Research Laboratory, Department of Chemistry, Oxford Centre for Integrative Systems Biology, University of Oxford, Mansfield Road, Oxford OX1 3TA, UK.
authors: Martine I
authors: MI
authors: Abboud
authors: Chemistry Research Laboratory, Department of Chemistry, Oxford Centre for Integrative Systems Biology, University of Oxford, Mansfield Road, Oxford OX1 3TA, UK.
authors: Wei
authors: W
authors: Ge
authors: Chemistry Research Laboratory, Department of Chemistry, Oxford Centre for Integrative Systems Biology, University of Oxford, Mansfield Road, Oxford OX1 3TA, UK.
authors: Carmen
authors: C
authors: Domene
authors: UMR8576 CNRS-Lille University, Villeneuve d'Ascq 59655, France.
authors: François-Xavier
authors: FX
authors: Cantrelle
authors: UMR8576 CNRS-Lille University, Villeneuve d'Ascq 59655, France.
authors: Isabelle
authors: I
authors: Landrieu
authors: Chemistry Research Laboratory, Department of Chemistry, Oxford Centre for Integrative Systems Biology, University of Oxford, Mansfield Road, Oxford OX1 3TA, UK.
authors: Adam P
authors: AP
authors: Hardy
authors: Nuffield Department of Clinical Medicine, University of Oxford, Henry Wellcome Building for Molecular Physiology, Roosevelt Drive, Oxford OX3 7BN, UK.
authors: Christopher W
authors: CW
authors: Pugh
authors: Nuffield Department of Clinical Medicine, University of Oxford, Henry Wellcome Building for Molecular Physiology, Roosevelt Drive, Oxford OX3 7BN, UK.|Ludwig Institute for Cancer Research, University of Oxford, Roosevelt Drive, Oxford OX3 7DQ, UK.
authors: Peter J
authors: PJ
authors: Ratcliffe
authors: Chemistry Research Laboratory, Department of Chemistry, Oxford Centre for Integrative Systems Biology, University of Oxford, Mansfield Road, Oxford OX1 3TA, UK.
authors: Timothy D W
authors: TD
authors: Claridge
authors: Chemistry Research Laboratory, Department of Chemistry, Oxford Centre for Integrative Systems Biology, University of Oxford, Mansfield Road, Oxford OX1 3TA, UK.
authors: Christopher J
authors: CJ
authors: Schofield
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D018360:Crystallography, X-Ray; D005347:Fibroblasts; D006801:Humans; D006900:Hydroxylation; D000860:Hypoxia / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000737:chemistry / Q000378:metabolism*; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D007527:Isoenzymes / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D051379:Mice; D056004:Molecular Dynamics Simulation; D009369:Neoplasms / Q000235:genetics; D010100:Oxygen / Q000378:metabolism; D011086:Polycythemia / Q000151:congenital / Q000235:genetics; D011392:Proline / Q000378:metabolism; D011485:Protein Binding / Q000235:genetics; D000072417:Protein Domains / Q000235:genetics; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007527:Isoenzymes; D011994:Recombinant Proteins; D011392:Proline; C490190:EGLN1 protein, human; C488894:EGLN3 protein, human; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D010100:Oxygen