Structural basis for oxygen degradation ...
Document type :
Article dans une revue scientifique
DOI :
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Title :
Structural basis for oxygen degradation domain selectivity of the HIF prolyl hydroxylases
Author(s) :
Chowdhury, Rasheduzzaman [Auteur]
Chemistry Research Laboratory [Oxford, UK]
Leung, Ivanhoe K. H. [Auteur]
Chemistry Research Laboratory [Oxford, UK]
Tian, Ya-Min [Auteur]
Nuffield Department of Clinical Medicine [Oxford]
Abboud, Martine I. [Auteur]
Chemistry Research Laboratory [Oxford, UK]
Ge, Wei [Auteur]
Chemistry Research Laboratory [Oxford, UK]
Domene, Carmen [Auteur]
Chemistry Research Laboratory [Oxford, UK]
Cantrelle, Francois-Xavier [Auteur]
Unité de Glycobiologie Structurale et Fonctionnelle - UMR 8576 [UGSF]
Landrieu, Isabelle [Auteur]
Unité de Glycobiologie Structurale et Fonctionnelle - UMR 8576 [UGSF]
Hardy, Adam P. [Auteur]
Chemistry Research Laboratory [Oxford, UK]
Pugh, Christopher W. [Auteur]
Nuffield Department of Clinical Medicine [Oxford]
Ratcliffe, Peter J. [Auteur]
Nuffield Department of Clinical Medicine [Oxford]
Claridge, Timothy D. W. [Auteur]
Chemistry Research Laboratory [Oxford, UK]
Schofield, Christopher J. [Auteur]
Chemistry Research Laboratory [Oxford, UK]
Chemistry Research Laboratory [Oxford, UK]
Leung, Ivanhoe K. H. [Auteur]
Chemistry Research Laboratory [Oxford, UK]
Tian, Ya-Min [Auteur]
Nuffield Department of Clinical Medicine [Oxford]
Abboud, Martine I. [Auteur]
Chemistry Research Laboratory [Oxford, UK]
Ge, Wei [Auteur]
Chemistry Research Laboratory [Oxford, UK]
Domene, Carmen [Auteur]
Chemistry Research Laboratory [Oxford, UK]
Cantrelle, Francois-Xavier [Auteur]

Unité de Glycobiologie Structurale et Fonctionnelle - UMR 8576 [UGSF]
Landrieu, Isabelle [Auteur]

Unité de Glycobiologie Structurale et Fonctionnelle - UMR 8576 [UGSF]
Hardy, Adam P. [Auteur]
Chemistry Research Laboratory [Oxford, UK]
Pugh, Christopher W. [Auteur]
Nuffield Department of Clinical Medicine [Oxford]
Ratcliffe, Peter J. [Auteur]
Nuffield Department of Clinical Medicine [Oxford]
Claridge, Timothy D. W. [Auteur]
Chemistry Research Laboratory [Oxford, UK]
Schofield, Christopher J. [Auteur]
Chemistry Research Laboratory [Oxford, UK]
Journal title :
Nature communications
Volume number :
7
Pages :
12673
Publication date :
2016-08-26
ISSN :
2041-1723
HAL domain(s) :
Chimie/Chimie théorique et/ou physique
English abstract : [en]
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 ...
Show more >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.Show less >
Show more >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.Show less >
Language :
Anglais
Audience :
Non spécifiée
Administrative institution(s) :
CNRS
Université de Lille
Université de Lille
Research team(s) :
RMN et interactions moléculaires
Submission date :
2020-02-12T15:44:52Z
2021-02-26T08:24:12Z
2021-02-26T08:24:12Z
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