Hypoxia-inducible factor 1-alpha oxygen-dependent degradation domain (HIF-1α ODD) (HIF-1α ODD)

The Hypoxia-inducible factor 1-alpha (HIF-1α) oxygen-dependent degradation (ODD) domain is a critical regulatory region within the HIF-1α protein that mediates its rapid degradation under normoxic conditions [1]. This domain contains specific proline residues (Pro402 and Pro564) that are hydroxylated by prolyl hydroxylase domain (PHD) enzymes in the presence of oxygen [3, 4]. Once hydroxylated, the ODD domain is recognized by the von Hippel-Lindau (VHL) tumor suppressor protein, which acts as part of an E3 ubiquitin ligase complex to target HIF-1α for proteasomal degradation [2]. In hypoxic environments, the lack of oxygen inhibits PHD activity, allowing HIF-1α to escape degradation, accumulate, and translocate to the nucleus to activate genes involved in erythropoiesis, angiogenesis, and anaerobic metabolism [5]. This domain is a focal point for therapeutic intervention; PHD inhibitors stabilize HIF-1α by preventing ODD-mediated degradation to treat anemia, while strategies to enhance its degradation or use the domain for hypoxia-targeted gene delivery are explored for cancer therapy [4, 5].

Other names

ODD domainHIF-1α ODD domainOxygen-dependent degradation domain of HIF-1 alphaHIF1A ODD

Inhibition of prolyl hydroxylase (PHD) enzymes prevents the hydroxylation of proline residues within the ODD domain, which blocks the binding of the von Hippel-Lindau (VHL) E3 ubiquitin ligase and prevents the subsequent proteasomal degradation of HIF-1α [2, 3, 5].