2zgd

From Proteopedia

Revision as of 06:15, 13 February 2008

Asn-hydroxylation stabilises the ankyrin repeat domain fold

Overview

The stability and activity of hypoxia-inducible factor (HIF) are regulated, by the post-translational hydroxylation of specific prolyl and asparaginyl, residues. We show that the HIF asparaginyl hydroxylase, factor inhibiting, HIF (FIH), also catalyzes hydroxylation of highly conserved asparaginyl, residues within ankyrin repeat (AR) domains (ARDs) of endogenous Notch, receptors. AR hydroxylation decreases the extent of ARD binding to FIH, while not affecting signaling through the canonical Notch pathway. ARD, proteins were found to efficiently compete with HIF for FIH-dependent, hydroxylation. Crystallographic analyses of the hydroxylated Notch ARD, (2.35A) and of Notch peptides bound to FIH (2.4-2.6A) reveal the, stereochemistry of hydroxylation on the AR and imply that significant, conformational changes are required in the ARD fold in order to enable, hydroxylation at the FIH active site. We propose that ARD proteins, function as natural inhibitors of FIH and that the hydroxylation status of, these proteins provides another oxygen-dependent interface that modulates, HIF signaling.

About this Structure

2ZGD is a Single protein structure of sequence from [1] with and as ligands. Known structural/functional Sites: , , , , , and . Full crystallographic information is available from OCA.

Reference

Asparaginyl hydroxylation of the Notch ankyrin repeat domain by factor inhibiting hypoxia-inducible factor., Coleman ML, McDonough MA, Hewitson KS, Coles C, Mecinovic J, Edelmann M, Cook KM, Cockman ME, Lancaster DE, Kessler BM, Oldham NJ, Ratcliffe PJ, Schofield CJ, J Biol Chem. 2007 Aug 17;282(33):24027-38. Epub 2007 Jun 15. PMID:17573339

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