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Structural basis for the recognition of hydroxyproline in HIF-1α by pVHL

Author

Listed:
  • Wai-Ching Hon

    (Henry Wellcome Building of Genomic Medicine)

  • Michael I. Wilson

    (Henry Wellcome Building of Genomic Medicine
    MRC Laboratory of Molecular Biology)

  • Karl Harlos

    (Henry Wellcome Building of Genomic Medicine)

  • Timothy D. W. Claridge

    (Oxford Centre for Molecular Sciences and Dyson Perrins Laboratory)

  • Christopher J. Schofield

    (Oxford Centre for Molecular Sciences and Dyson Perrins Laboratory)

  • Christopher W. Pugh

    (Henry Wellcome Building of Genomic Medicine)

  • Patrick H. Maxwell

    (Henry Wellcome Building of Genomic Medicine)

  • Peter J. Ratcliffe

    (Henry Wellcome Building of Genomic Medicine)

  • David I. Stuart

    (Henry Wellcome Building of Genomic Medicine)

  • E. Yvonne Jones

    (Henry Wellcome Building of Genomic Medicine)

Abstract

Hypoxia-inducible factor-1 (HIF-1) is a transcriptional complex that controls cellular and systemic homeostatic responses to oxygen availability1. HIF-1α is the oxygen-regulated subunit of HIF-1, an αβ heterodimeric complex1. HIF-1α is stable in hypoxia, but in the presence of oxygen it is targeted for proteasomal degradation by the ubiquitination complex pVHL, the protein of the von Hippel–Lindau (VHL) tumour suppressor gene and a component of an E3 ubiquitin ligase complex2,3. Capture of HIF-1α by pVHL is regulated by hydroxylation of specific prolyl residues in two functionally independent regions of HIF-1α4,5,6,7. The crystal structure of a hydroxylated HIF-1α peptide bound to VCB (pVHL, elongins C and B) and solution binding assays reveal a single, conserved hydroxyproline-binding pocket in pVHL. Optimized hydrogen bonding to the buried hydroxyprolyl group confers precise discrimination between hydroxylated and unmodified prolyl residues. This mechanism provides a new focus for development of therapeutic agents to modulate cellular responses to hypoxia.

Suggested Citation

  • Wai-Ching Hon & Michael I. Wilson & Karl Harlos & Timothy D. W. Claridge & Christopher J. Schofield & Christopher W. Pugh & Patrick H. Maxwell & Peter J. Ratcliffe & David I. Stuart & E. Yvonne Jones, 2002. "Structural basis for the recognition of hydroxyproline in HIF-1α by pVHL," Nature, Nature, vol. 417(6892), pages 975-978, June.
    • Handle: RePEc:nat:nature:v:417:y:2002:i:6892:d:10.1038_nature00767
    DOI: 10.1038/nature00767
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    Cited by:

    1. Francisco R Fields & Niraja Suresh & Morgan Hiller & Stefan D Freed & Kasturi Haldar & Shaun W Lee, 2020. "Algorithmic assessment of missense mutation severity in the Von-Hippel Lindau protein," PLOS ONE, Public Library of Science, vol. 15(11), pages 1-19, November.
    2. Tom Dixon & Derek MacPherson & Barmak Mostofian & Taras Dauzhenka & Samuel Lotz & Dwight McGee & Sharon Shechter & Utsab R. Shrestha & Rafal Wiewiora & Zachary A. McDargh & Fen Pei & Rajat Pal & João , 2022. "Predicting the structural basis of targeted protein degradation by integrating molecular dynamics simulations with structural mass spectrometry," Nature Communications, Nature, vol. 13(1), pages 1-24, December.
    3. Tsering Palmo & Bilal Ahmed Abbasi & Neha Chanana & Kavita Sharma & Mohammed Faruq & Tashi Thinlas & Malik Z. Abdin & Qadar Pasha, 2022. "The EDN1 Missense Variant rs5370 G > T Regulates Adaptation and Maladaptation under Hypobaric Hypoxia," IJERPH, MDPI, vol. 19(18), pages 1-13, September.

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