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

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 and E. Yvonne Jones ()
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Wai-Ching Hon: Henry Wellcome Building of Genomic Medicine
Michael I. Wilson: Henry Wellcome Building of Genomic Medicine
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

Nature, 2002, vol. 417, issue 6892, 975-978

Abstract: 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.

Date: 2002
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DOI: 10.1038/nature00767

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