Hydroxylation of HIF-α. HIF-α contains bHLH and PAS DNA-binding and heterodimerization domains as well as two modular transcriptional activation domains (N-TAD and C-TAD). In the presence of oxygen, HIF-α is hydroxylated on conserved prolyl residues within the ODD (note that only one of two potential hydroxylation sites is shown for simplicity) by members of the EGLN family and on a conserved asparaginyl residue within the C-TAD by FIH1. The former leads to the recruitment of the pVHL ubiquitin ligase complex and the latter to displacement of p300 and CBP coactivator proteins. Polyubiquitination by the pVHL complex, which contains Elongin B, Elongin C, Rbx1, Cul2, and an unidentified E2 ubiquitin-conjugating enzyme, leads to proteasomal degradation of HIF. Recruitment of the E2 is linked to neddylation of the Cul2 scaffolding protein. Note that the HIF-α residues that are ubiquitinated are not known. B, Elongin B; C, Elongin C; ?E2, unidentified E2 ubiquitin-conjugating enzyme; N8, Nedd8; OH, hydroxy group; P, prolyl residue; N, aspariginyl residue; Ub, ubiguitin; ODD, oxygen-dependent degradation domain.