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 today 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.
Nuclear receptors are proteins that directly bind DNA to turn genes on or off in response to outside signals. For some of the 48 members of this protein family, it’s well known what sets them in motion and what genes they activate or inactivate. The estrogen receptor, for example, is a nuclear receptor that receives estrogen, the female hormone, and switches on genes that drive female characteristics. For other nuclear receptors, the orphans, all we really know is that they resemble other family members. Their function and their binding partners remain a mystery.
“We are interested in how a subset of the nuclear receptor family works – the orphans. Even though some of these receptors have thousands of publications already, there are still dozens that very few people work on,” Dr. Rastinejad explains. “We don’t have a clue what their natural binding partners are or what genes they regulate. But they’re all part of the nuclear receptor family, so there’s a lot of excitement every time a new one is uncovered.”