Structural Basis of Natural Promoter Recognition by a Unique Nuclear Receptor, HNF4alpha. Diabetes Gene Product

Overview

Journal J Biol Chem

Specialty Biochemistry

Date 2008 Oct 3

PMID 18829458

Citations 18

Authors

Peng Lu

Geun Bae Rha

Manana Melikishvili

Guangteng Wu

Brandon C Adkins

Michael G Fried

Young-In Chi

Affiliations

Soon will be listed here.

Abstract

HNF4alpha (hepatocyte nuclear factor 4alpha) plays an essential role in the development and function of vertebrate organs, including hepatocytes and pancreatic beta-cells by regulating expression of multiple genes involved in organ development, nutrient transport, and diverse metabolic pathways. As such, HNF4alpha is a culprit gene product for a monogenic and dominantly inherited form of diabetes, known as maturity onset diabetes of the young (MODY). As a unique member of the nuclear receptor superfamily, HNF4alpha recognizes target genes containing two hexanucleotide direct repeat DNA-response elements separated by one base pair (DR1) by exclusively forming a cooperative homodimer. We describe here the 2.0 angstroms crystal structure of human HNF4alpha DNA binding domain in complex with a high affinity promoter element of another MODY gene, HNF1alpha, which reveals the molecular basis of unique target gene selection/recognition, DNA binding cooperativity, and dysfunction caused by diabetes-causing mutations. The predicted effects of MODY mutations have been tested by a set of biochemical and functional studies, which show that, in contrast to other MODY gene products, the subtle disruption of HNF4alpha molecular function can cause significant effects in afflicted MODY patients.

Citing Articles

Functional characterization of HNF4A gene variants identify promoter and cell line specific transactivation effects.

Kaci A, Solheim M, Silgjerd T, Hjaltadottir J, Hornnes L, Molnes J Hum Mol Genet. 2024; 33(10):894-904.

PMID: 38433330 PMC: 11070132. DOI: 10.1093/hmg/ddae027.

The protein architecture and allosteric landscape of HNF4α.

Rastinejad F Front Endocrinol (Lausanne). 2023; 14:1219092.

PMID: 37732120 PMC: 10507258. DOI: 10.3389/fendo.2023.1219092.

Structural insights into the HNF4 biology.

Beinsteiner B, Billas I, Moras D Front Endocrinol (Lausanne). 2023; 14:1197063.

PMID: 37404310 PMC: 10315846. DOI: 10.3389/fendo.2023.1197063.

A Review of Functional Characterization of Single Amino Acid Change Mutations in HNF Transcription Factors in MODY Pathogenesis.

Cubuk H, Yalcin Capan O Protein J. 2021; 40(3):348-360.

PMID: 33950347 DOI: 10.1007/s10930-021-09991-8.

ErbB3-binding protein 1 (EBP1) represses HNF4α-mediated transcription and insulin secretion in pancreatic β-cells.

Han E, Singh P, Lee I, Urrutia R, Chi Y J Biol Chem. 2019; 294(38):13983-13994.

PMID: 31362984 PMC: 6755798. DOI: 10.1074/jbc.RA119.009558.

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