Structure of HIF-1α and the oxygen-dependent regulation of HIF-1α protein stabilisation and activation: The N-terminal regions contain the basic helix-loop-helix (bHLH) domain involved in DNA-binding and the Per-Arnt-Sim (PAS) A and B domains required for heterodimerisation with HIF-1β. The oxygen-dependent degradation domain (ODD) is where PHD2 hydroxylates proline residues P402 and P562, which enables binding of VHL and proteosomal degradation. The terminal transcriptional activation domains (TADs) are responsible for transactivation of target genes. The N-TAD is located towards the N-terminus, with the C-TAD located at the extreme C-terminus. Factor inhibiting HIF-1 (FIH-1) hydroxylates asparagine H803 in the C-TAD, preventing the binding of coactivators CBP/p300, thus inhibiting activation of HIF-1α. Both hydroxylation processes use 2-oxoglutarate (2-OG) and O2 as substrates and produce succinate and carbon dioxide (CO2) as byproducts.
