Erythrocytosis-inducing PHD2 mutations implicate biological role for N-terminal prolyl-hydroxylation in HIF1α oxygen-dependent degradation domain.

ABSTRACT: Mutations in EGLN1, the gene encoding for hypoxia-inducible factor (HIF) prolyl-4-hydroxylase 2 (PHD2), cause erythrocytosis and in rare cases the development of neuroendocrine tumors. In the presence of oxygen, PHD2 hydroxylates one or both conserved prolines in the oxygen-dependent degradation domain (ODD) of HIFα subunits, sufficiently marking HIFα for binding and ubiquitylation via the von Hippel-Lindau (VHL) tumor suppressor protein-containing E3 ubiquitin ligase and subsequent degradation by the 26S proteasome. However, prolyl-hydroxylation in the C-terminal ODD appears to be the predominant and sufficient event in triggering the oxygen-dependent destruction of HIFα, rendering the biological significance of N-terminal ODD proline unclear. Here, we examined seven disease-associ

SUBMITTER: Taber CC 

PROVIDER: S-EPMC12537007 | biostudies-literature | 2025 Oct

REPOSITORIES: biostudies-literature