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Structural basis for the recognition of hydroxyproline in alpha IF-1 alpha by pVHL

Hon, WC; Wilson, MI; Harlos, K; Claridge, TDW; Schofield, CJ; Pugh, CW; ... Jones, EY; + view all (2002) Structural basis for the recognition of hydroxyproline in alpha IF-1 alpha by pVHL. NATURE , 417 (6892) 975 - 978.

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Abstract

Hypoxia-inducible factor-1 (HIF-1) is a transcriptional complex that controls cellular and systemic homeostatic responses to oxygen availability(1). HIF-1alpha is the oxygen-regulated subunit of HIF-1, an alphabeta heterodimeric complex(1). HIF-1alpha 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 complex(2,3). Capture of HIF-1alpha by pVHL is regulated by hydroxylation of specific prolyl residues in two functionally independent regions of HIF-1alpha(4-7). The crystal structure of a hydroxylated HIF-1alpha 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.

Type:Article
Title:Structural basis for the recognition of hydroxyproline in alpha IF-1 alpha by pVHL
Keywords:HYPOXIA-INDUCIBLE FACTOR-1, PROLYL HYDROXYLATION, PROLINE HYDROXYLATION, HIF-ALPHA, PROTEIN, VHL, COMPLEX, DESTRUCTION, PROTEOLYSIS, SOFTWARE
UCL classification:UCL > School of Life and Medical Sciences > Faculty of Medical Sciences > Medicine (Division of)

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