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. 2002 Jun 7;296(5574):1886-9.
doi: 10.1126/science.1073440. Epub 2002 May 9.

Structure of an HIF-1alpha -pVHL complex: hydroxyproline recognition in signaling

Jung-Hyun Min  1 , Haifeng Yang, Mircea Ivan, Frank Gertler, William G Kaelin Jr, Nikola P Pavletich
Affiliations

Structure of an HIF-1alpha -pVHL complex: hydroxyproline recognition in signaling

Jung-Hyun Min et al. Science. .

Abstract

The ubiquitination of the hypoxia-inducible factor (HIF) by the von Hippel-Lindau tumor suppressor (pVHL) plays a central role in the cellular response to changes in oxygen availability. pVHL binds to HIF only when a conserved proline in HIF is hydroxylated, a modification that is oxygen-dependent. The 1.85 angstrom structure of a 20-residue HIF-1alpha peptide-pVHL-ElonginB-ElonginC complex shows that HIF-1alpha binds to pVHL in an extended beta strand-like conformation. The hydroxyproline inserts into a gap in the pVHL hydrophobic core, at a site that is a hotspot for tumorigenic mutations, with its 4-hydroxyl group recognized by buried serine and histidine residues. Although the beta sheet-like interactions contribute to the stability of the complex, the hydroxyproline contacts are central to the strict specificity characteristic of signaling.

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