The nuclear receptor HNF-4α is an important transcriptional regulator of liver and pancreatic genes and its dysfunction has been linked to maturity-onset diabetes of the young, kidney failure and metabolic syndrome. Fraydoon Rastinejad and colleagues describe a crystal structure of the multidomain HNF-4α homodimer bound to its DNA response element and coactivator-derived peptides. The structure reveals a domain convergence centre connecting multiple domains and serving as an allosteric transmission system for propagating signals between the ligand-binding and DNA-binding domains. The architecture of HNF-4α is compared to the only other known structure of a multidomain nuclear receptor complex, that of PPAR-γ–RXR-α.
Researchers have determined the complete three-dimensional structure of a protein called HNF-4α. HNF-4α controls gene expression in the liver and pancreas, switching genes on or off as needed. People with mature onset diabetes of the young (MODY1) a rare form of the disease, have inherited mutations in the HNF-4α protein. This first-ever look at HNF-4α’s full structure, published in Nature, uncovers new information about how it functions. The study also reveals new pockets in the protein that could be targeted with therapeutic drugs aimed at alleviating MODY1.
“Previous structural studies of HNF-4α and related nuclear receptors only revealed smaller, isolated fragments of these proteins,” said Fraydoon Rastinejad, Ph.D., professor in Sanford-Burnham’s Diabetes and Obesity Research Center, located at the Institute’s Lake Nona campus in Orlando, Fla., and senior author of the study.
“Because those studies looked only at separate pieces of HNF-4α, many people suspected there was no coordination between different regions of the protein. But we showed those assumptions are incorrect. HNF-4α’s domains are highly organized in a way that has implications for our understanding of MODY1 and the development of treatments for the disease.”