Leu‐574 of human HIF‐1α is a molecular determinant of prolyl hydroxylation
- 14 April 2004
- journal article
- Published by Wiley in The FASEB Journal
- Vol. 18 (9) , 1028-1030
- https://doi.org/10.1096/fj.03-1233fje
Abstract
SPECIFIC AIMSHIF-1α is constantly degraded in normoxia via the ubiquitin–proteasome pathway. The von Hippel-Lindau (VHL) E3 ubiquitin ligase binds HIF-1α through specific recognition of hydroxyprolines that are modified by the oxygen-dependent HIF prolyl hydroxylases (PHDs/HPHs). Despite the identification of a conserved Leu-X-X-Leu-Ala-Pro motif, the molecular requirement of HIF-1α for PHDs/HPHs binding remains elusive. We recently demonstrated that Leu-574 of human HIF-1α, 10 residues downstream of Pro-564, is essential for VHL recognition and protein degradation. In light of its nonessential role in direct contact with the VHL protein, we investigated the involvement of Leu-574 in prolyl hydroxylation and PHD/HPH recruitment.PRINCIPAL FINDINGS1. Leu-574 is required for HIF-1α instabilityWe have reported that mutation or deletion of Leu-574 in human HIF-1α gave rise to the stabilization of carboxyl-terminal, oxygen-dependent degradation domain (C-ODD, amino acids 498-603), resulting from the loss of VHL...Keywords
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