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Chemical Basis for the Selectivity of the von Hippel Lindau Tumor Suppressor pVHL for Prolyl-Hydroxylated HIF-1α

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journal contribution
posted on 17.08.2010, 00:00 by Christopher J. R. Illingworth, Christoph Loenarz, Christopher J. Schofield, Carmen Domene
In animals, the post-translational hydroxylation of hypoxia inducible factor (HIF) is a central mechanism for regulating gene expression in an oxygen-dependent manner. The oxygenase-catalyzed trans-4-prolyl hydroxylation of HIF-α increases its affinity for the von Hippel Lindau protein elongin B/C (VCB) ubiquitin ligase complex, leading to HIF-α degradation. The level of binding of HIF-α to VCB is increased by ∼1000-fold upon addition of a single oxygen atom to a conserved proline residue. Here, we describe computational studies on the chemical basis of this “switchlike” signaling event. The results support crystallographic analyses showing the importance of hydrogen bonding in the binding of hydroxylated HIF-α to VCB and suggest that trans 4-hydroxylation “preorganizes” the proline residue to adopt the C4-exo conformation, via operation of the stereoelectronic gauche effect.