InterPro domain: IPR027445

Mammalian cells adapt to hypoxic conditions through a transcriptional response pathway mediated by hypoxia-inducible factor (HIF). HIF is composed of a heterodimer of alpha and beta subunits. Hypoxia-inducible factor 1-alpha inhibitor (FIH-1) regulates HIF-1 alpha (HIF1A) transcriptional activity by hydrolyses an asparagine residue within the HIF1A C-terminal transactivation domain. This prevents interation of HIF1A with its coactivators including Cbp/p300-interacting transactivator [ 1 , 2 , 3 , 4 ].

It also has been shown that FIH-1 hydrolyses asparagine residues within ankyrin repeat domains (ARD) of ARD-containing proteins such as NFKB1, NFKBIA, NOTCH1, ASB4 and PPP1R12A [ 5 , 6 , 7 ]. FIH bind more tightly to ARD-cotaining proteins than HIF which suggests that the ARD family lead to competitive inhibition of FIH-dependent HIF hydroxylation [ 8 ].

1. FIH-1: a novel protein that interacts with HIF-1alpha and VHL to mediate repression of HIF-1 transcriptional activity. Genes Dev. 15, 2675-86
2. Regulation of hypoxia-inducible factor 1 by prolyl and asparaginyl hydroxylases. Biochem. Biophys. Res. Commun. 338, 610-6
3. Signalling hypoxia by HIF hydroxylases. Biochem. Biophys. Res. Commun. 338, 617-26
4. Regulation of HIF: prolyl hydroxylases. Novartis Found. Symp. 272, 15-25; discussion 25-36
5. Asparaginyl hydroxylation of the Notch ankyrin repeat domain by factor inhibiting hypoxia-inducible factor. J. Biol. Chem. 282, 24027-38
6. Factor-inhibiting hypoxia-inducible factor (FIH) catalyses the post-translational hydroxylation of histidinyl residues within ankyrin repeat domains. FEBS J. 278, 1086-97
7. Asparagine and aspartate hydroxylation of the cytoskeletal ankyrin family is catalyzed by factor-inhibiting hypoxia-inducible factor. J. Biol. Chem. 286, 7648-60
8. Signalling cross talk of the HIF system: involvement of the FIH protein. Curr. Pharm. Des. 15, 3904-7