Structural basis for oxygen degradation domain selectivity of the HIF prolyl hydroxylases

Show simple item record Chowdhury, R en Leung, Ka Ho Ivanhoe en Tian, Y-M en Abboud, MI en Ge, W en Domene, C en Cantrelle, F-X en Landrieu, I en Hardy, AP en Pugh, CW en Ratcliffe, PJ en Claridge, TDW en Schofield, CJ en 2016-10-17T04:05:00Z en 2016-08-26 en
dc.identifier.issn 2041-1723 en
dc.identifier.uri en
dc.description.abstract The response to hypoxia in animals involves the expression of multiple genes regulated by the αβ-hypoxia-inducible transcription factors (HIFs). The hypoxia-sensing mechanism involves oxygen limited hydroxylation of prolyl residues in the N- and C-terminal oxygen-dependent degradation domains (NODD and CODD) of HIFα isoforms, as catalysed by prolyl hydroxylases (PHD 1–3). Prolyl hydroxylation promotes binding of HIFα to the von Hippel–Lindau protein (VHL)–elongin B/C complex, thus signalling for proteosomal degradation of HIFα. We reveal that certain PHD2 variants linked to familial erythrocytosis and cancer are highly selective for CODD or NODD. Crystalline and solution state studies coupled to kinetic and cellular analyses reveal how wild-type and variant PHDs achieve ODD selectivity via different dynamic interactions involving loop and C-terminal regions. The results inform on how HIF target gene selectivity is achieved and will be of use in developing selective PHD inhibitors. en
dc.publisher Nature Publishing Group: Nature Communications en
dc.relation.ispartofseries Nature Communications en
dc.rights Items in ResearchSpace are protected by copyright, with all rights reserved, unless otherwise indicated. Previously published items are made available in accordance with the copyright policy of the publisher. Details obtained from en
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dc.title Structural basis for oxygen degradation domain selectivity of the HIF prolyl hydroxylases en
dc.type Journal Article en
dc.identifier.doi 10.1038/ncomms12673 en
pubs.volume 7 en
dc.description.version VoR - Version of Record en
dc.rights.holder Copyright: The authors en
dc.identifier.pmid 27561929 en
dc.rights.accessrights en
pubs.subtype Article en
pubs.elements-id 540445 en Science en Chemistry en
pubs.number 12673 en
pubs.record-created-at-source-date 2016-08-27 en 2016-08-26 en
pubs.dimensions-id 27561929 en

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