Chemical Basis for the Selectivity of the von Hippel Lindau Tumor Suppressor pVHL for Prolyl-Hydroxylated HIF-1α
Christopher J. R. Illingworth
Christoph Loenarz
Christopher J. Schofield
Carmen Domene
10.1021/bi100358t.s001
https://acs.figshare.com/articles/journal_contribution/Chemical_Basis_for_the_Selectivity_of_the_von_Hippel_Lindau_Tumor_Suppressor_pVHL_for_Prolyl_Hydroxylated_HIF_1_/2742229
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 <i>trans</i>-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 <i>trans</i> 4-hydroxylation “preorganizes” the proline residue to adopt the C<sup>4</sup>-<i>exo</i> conformation, via operation of the stereoelectronic gauche effect.
2010-08-17 00:00:00
HIF
proline residue
hypoxia inducible factor
von Hippel Lindau Tumor Suppressor pVHL
hydroxylation
VCB