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The aspariginyl hydroxylase human factor inhibiting hypoxia-inducible factor (FIH) is an important regulator of the transcriptional activity of hypoxia-inducible factor. FIH also catalyzes the hydroxylation of asparaginyl and other residues in ankyrin repeat domain-containing proteins, including apoptosis stimulating of p53 protein (ASPP) family members. ASPP2 is reported to undergo a single FIH-catalyzed hydroxylation at Asn-986. We report biochemical and crystallographic evidence showing that FIH catalyzes the unprecedented post-translational hydroxylation of both asparaginyl residues in "VNVN" and related motifs of ankyrin repeat domains in ASPPs (i.e., ASPP1, ASPP2, and iASPP) and the related ASB11 and p18-INK4C proteins. Our biochemical results extend the substrate scope of FIH catalysis and may have implications for its biological roles, including in the hypoxic response and ASPP family function.

Original publication

DOI

10.1016/j.jbc.2022.102020

Type

Journal article

Journal

J Biol Chem

Publication Date

06/2022

Volume

298

Keywords

JmjC demethylase, ankyrin, epigenetics, factor inhibiting HIF, hypoxia-inducible factor, iron and 2-oxoglutarate/alpha-ketoglutarate oxygenase, post-translational modification/hydroxylation, Adaptor Proteins, Signal Transducing, Amino Acid Sequence, Ankyrin Repeat, Apoptosis Regulatory Proteins, Catalysis, Humans, Hydroxylation, Hypoxia, Mixed Function Oxygenases, Repressor Proteins