Structural basis of natural promoter recognition by a unique nuclear receptor, HNF4α: Diabetes gene product

Peng Lu, Geun Bae Rha, Manana Melikishvili, Guangteng Wu, Brandon C. Adkins, Michael G. Fried, Young In Chi

Research output: Contribution to journalArticlepeer-review

23 Scopus citations

Abstract

HNF4α (hepatocyte nuclear factor 4α) plays an essential role in the development and function of vertebrate organs, including hepatocytes and pancreatic β-cells by regulating expression of multiple genes involved in organ development, nutrient transport, and diverse metabolic pathways. As such, HNF4α 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, HNF4α 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 Å crystal structure of human HNF4α DNA binding domain in complex with a high affinity promoter element of another MODY gene, HNF1α, 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 HNF4α molecular function can cause significant effects in afflicted MODY patients.

Original languageEnglish (US)
Pages (from-to)33685-33697
Number of pages13
JournalJournal of Biological Chemistry
Volume283
Issue number48
DOIs
StatePublished - Nov 28 2008

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