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

被引：106

作者：

Chowdhury, Rasheduzzaman ^{[1
]}

Leung, Ivanhoe K. H. ^{[1
,5
]}

Tian, Ya-Min ^{[2
]}

Abboud, Martine I. ^{[1
]}

Ge, Wei ^{[1
]}

Domene, Carmen ^{[1
,6
]}

Cantrelle, Francois-Xavier ^{[3
]}

Landrieu, Isabelle ^{[3
]}

Hardy, Adam P. ^{[1
]}

Pugh, Christopher W. ^{[2
]}

Ratcliffe, Peter J. ^{[2
,4
]}

Claridge, Timothy D. W. ^{[1
]}

Schofield, Christopher J. ^{[1
]}

机构：

[1] Univ Oxford, Oxford Ctr Integrat Syst Biol, Dept Chem, Chem Res Lab, Mansfield Rd, Oxford OX1 3TA, England

[2] Univ Oxford, Nuffield Dept Clin Med, Henry Wellcome Bldg Mol Physiol,Roosevelt Dr, Oxford OX3 7BN, England

[3] Univ Lille, CNRS, UMR8576, F-59655 Villeneuve Dascq, France

[4] Univ Oxford, Ludwig Inst Canc Res, Roosevelt Dr, Oxford OX3 7DQ, England

[5] Univ Auckland, Sch Chem Sci, Private Bag 92019, Auckland 1142, New Zealand

[6] Kings Coll London, Dept Chem, Britannia House,7 Trinity St, London SE1 1DB, England

来源：

NATURE COMMUNICATIONS | 2016年 / 7卷

基金：

英国生物技术与生命科学研究理事会; 英国惠康基金;

关键词：

HYPOXIA-INDUCIBLE-FACTOR; ERYTHROCYTOSIS ESTABLISHES; SLOW REACTION; PHD2; DYNAMICS; PATHWAY; FAMILY; HYDROXYPROLINE; RECOGNITION; HIF-1-ALPHA;

D O I：

10.1038/ncomms12673

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

The response to hypoxia in animals involves the expression of multiple genes regulated by the alpha beta-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 HIF alpha isoforms, as catalysed by prolyl hydroxylases (PHD 1-3). Prolyl hydroxylation promotes binding of HIFa to the von Hippel-Lindau protein (VHL)-elongin B/C complex, thus signalling for proteosomal degradation of HIFa. 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.

引用

页数：10

共 58 条

[21] CONSTANT-PRESSURE MOLECULAR-DYNAMICS SIMULATION - THE LANGEVIN PISTON METHOD [J].