Hepatocyte nuclear factor 4 is a transcription factor that constitutively binds fatty acids

被引：258

作者：

Wisely, GB ^{[1
]}

Miller, AB ^{[1
]}

Davis, RG ^{[1
]}

Thornquest, AD ^{[1
]}

Johnson, R ^{[1
]}

Spitzer, T ^{[1
]}

Sefler, A ^{[1
]}

Shearer, B ^{[1
]}

Moore, JT ^{[1
]}

Miller, AB ^{[1
]}

Willson, TM ^{[1
]}

Williams, SP ^{[1
]}

机构：

[1] GlaxoSmithKline Inc, Res Triangle Pk, NC 27709 USA

来源：

STRUCTURE | 2002年 / 10卷 / 09期

关键词：

diabetes; fatty acids; HNF4; MODY; nuclear receptor; transcription factor;

D O I：

10.1016/S0969-2126(02)00829-8

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

The 2.7 Angstrom X-ray crystal structure of the HNF4gamma ligand binding domain (LBD) revealed the presence of a fatty acid within the pocket, with the AF2 helix in a conformation characteristic of a transcriptionally active nuclear receptor. GC/MS and NMR analysis of chloroform/methanol extracts from purified HNF4alpha and HNF4gamma LBDs identified mixtures of saturated and cis-monounsaturated C14-18 fatty acids. The purified HNF4 LBDs interacted with nuclear receptor coactivators, and both HNF4 subtypes show high constitutive activity in transient transfection assays, which was reduced by mutations designed to interfere with fatty acid binding. The endogenous fatty acids did not readily exchange with radiolabeled palmitic acid, and all attempts to displace them without denaturing the protein failed. Our results suggest that the HNF4s may be transcription factors that are constitutively bound to fatty acids.

引用

页码：1225 / 1234

页数：10

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