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.
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Acknowledgements
We thank the staff at beamline ID14-2 of the ESRF, France. We are grateful to A. van der Merwe and A. Kearney for advice and assistance with the surface plasmon resonance experiments. L. M. McNeil assisted with the NMR analysis. This work was supported by Cancer Research UK and the Wellcome Trust. W.-C.H. and M.I.W. were recipients of a Human Frontiers long-term fellowship and a Natural Sciences and Engineering Research Council of Canada postdoctoral fellowship, respectively. The Medical Research Council supports C.W.P. and D.I.S., and Cancer Research UK supports E.Y.J.
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Hon, WC., Wilson, M., Harlos, K. et al. Structural basis for the recognition of hydroxyproline in HIF-1α by pVHL. Nature 417, 975–978 (2002). https://doi.org/10.1038/nature00767
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DOI: https://doi.org/10.1038/nature00767
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