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

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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
    Present address: School of Chemical Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand)

  • 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
    Present address: Department of Chemistry, King's College London, Britannia House, 7 Trinity Street, London SE1 1DB, UK)

  • 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
    Ludwig Institute for Cancer Research, 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)

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.

Suggested Citation

  • 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, 2016. "Structural basis for oxygen degradation domain selectivity of the HIF prolyl hydroxylases," Nature Communications, Nature, vol. 7(1), pages 1-10, November.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms12673
    DOI: 10.1038/ncomms12673
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    1. Wenguo Li & Junjiang Peng & Deqiang Yao & Bing Rao & Ying Xia & Qian Wang & Shaobai Li & Mi Cao & Yafeng Shen & Peixiang Ma & Rijing Liao & An Qin & Jie Zhao & Yu Cao, 2024. "The structural basis for the collagen processing by human P3H1/CRTAP/PPIB ternary complex," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    2. Tianshi Feng & Xuemei Zhao & Ping Gu & Wah Yang & Cunchuan Wang & Qingyu Guo & Qiaoyun Long & Qing Liu & Ying Cheng & Jin Li & Cynthia Kwan Yui Cheung & Donghai Wu & Xinyu Kong & Yong Xu & Dewei Ye & , 2022. "Adipocyte-derived lactate is a signalling metabolite that potentiates adipose macrophage inflammation via targeting PHD2," Nature Communications, Nature, vol. 13(1), pages 1-14, December.

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