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Biochemical and structural data reveals a site on ankyrin repeat domain proteins for double hydroxylation by Factor Inhibiting Hypoxia Inducible Factor (FIH).

Factor Inhibiting Hypoxia Inducible Factor (FIH) has an important role in the response to low oxygen (hypoxia) in animals. FIH adds a hydroxyl (-OH) group onto the master regulator Hypoxia Inducible Factor (HIF), which influences the ability of HIF to activate hundreds of genes that mediate the body’s response to hypoxia.

FIH also hydroxylates members of the ankyrin repeat domain protein family, including adding a single hydroxyl group to ASPP2 on asparagine 986. ASPP2 is involved in several aspects of cancer biology, including the regulation of cell polarity/adhesion and the transcriptional activity of the tumour suppressor protein p53. However, the effect of hydroxylation by FIH on ASPP2’s activity is still unclear.

Former Ludwig Oxford researcher Dr Thomas Leissing, working with the groups of Professor Christopher Schofield (Department of Chemistry) and Ludwig Oxford Professors Xin Lu and Peter Ratcliffe, used biochemical and structural biology techniques to further investigate the hydroxylation of ASPP2 and other ankyrin repeat domain proteins.

Unexpectedly, in addition to the known site of hydroxylation, the team uncovered the ability of FIH to add hydroxyl groups to both asparagine residues within the “VNVN” motif present in ASPP proteins. Further characterisation confirmed this to be a new type of post-translational hydroxylation.

Future work will define the potential role of this unprecedented modification by FIH in ankyrin repeat domain protein biology and in the response to hypoxia.

This research is published in the Journal of Biological Chemistry.

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