ORLANDO, Fla., March 13, 2013 – Researchers at Sanford-Burnham Medical Research
Institute (Sanford-Burnham) have determined the complete three-dimensional structure of a
protein called HNF-4a. HNF-4a 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-4a protein. This first-ever look at
HNF-4a’s full structure, published March 13 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-4a 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-4a, many people suspected there was no coordination between
different regions of the protein. But we showed those assumptions are incorrect. HNF-4a’s
domains are highly organized in a way that has implications for our understanding of
MODY1 and the development of treatments for the disease.”
Implications for MODY1
Rastinejad’s study helps explain why inherited genetic mutations that alter HNF-4a protein
structure can be so damaging. The mutations that lead to MODY1 usually occur within a
very small, specific region of the HNF-4a protein that is separate from the DNA-binding
region. Rastinejad and his team found that, despite their distant location, the mutations
telegraph a signal to the DNA-binding region, causing HNF-4a to malfunction and thus
MODY1 to develop.
The team also discovered new pockets in the HNF-4a protein that could be targeted with
therapeutic drugs. Like other nuclear receptors, HNF-4a has a pocket that binds natural
signaling molecules or could be targeted with synthetic drugs. But this new study revealed
several other pockets in other regions of the protein. And because they also found cross-
communication among different regions on the protein, the team believes that a drug binding
a distant pocket could still influence DNA binding.
“We’re now working with our colleagues in Sanford-Burnham’s Conrad Prebys Center for
Chemical Genomics to screen a large chemical library—a collection of around 300,000
compounds—to find molecules that bind to these newly discovered HNF-4a sites,”
Rastinejad said. “We’re looking for molecules that restore DNA binding in MODY1 patients.
This way, even if we can’t fix the mutation, we can still send a molecule to rescue the
receptor’s ability to tightly bind DNA.”
More about HNF-4a
HNF-4a is a special type of protein called a nuclear receptor. It sits on the DNA in a cell,
controlling thousands of genes by switching them on or off in response to outside signals.
Nuclear receptors make good drug targets because one region is bound to DNA, while a
pocket sits open on another part of the protein, just waiting to hold a signaling molecule.
Therapeutic drugs can also be made to fit these pockets, switching the nuclear receptor on or
off to alter gene expression.
Until this latest study, many researchers believed that most nuclear receptors are organized
like beads on a string. Each bead (protein domain) has a function, but the string itself is just
loose. Rastinejad and his team showed that the opposite is true. HNF-4a’s domains are
organized and coordinated—a domain that receives a signal can actually transmit it to a
distant site on the protein. According to Rastinejad, the domains are interconnected, talking
to one another.
HNF-4a is found mostly in liver and pancreatic cells, where it turns on genes needed by
those organs and keeps other, unnecessary genes off. HNF-4a helps control carbohydrate
metabolism, glucose regulation, insulin production, and many other important processes. In
other words, HNF-4a is what makes a liver a liver and a pancreas a pancreas.
This research was funded by National Institutes of Health—National Institute of Diabetes
and Digestive and Kidney Diseases grants R01DK094147and R01DK097475. The study was
co-authored by Vikas Chandra, Pengxiang Huang, Nalini Potluri, Dalei Wu, Youngchang
Kim, and Fraydoon Rastinejad. Kim is from Argonne National Laboratory; all other authors
are from Sanford-Burnham.
About Sanford-Burnham Medical Research Institute
Sanford-Burnham Medical Research Institute is dedicated to discovering the fundamental
molecular causes of disease and devising the innovative therapies of tomorrow. Sanford-
Burnham takes a collaborative approach to medical research with major programs in cancer,
neurodegeneration, diabetes, and infectious, inflammatory, and childhood diseases. The
Institute is recognized for its National Cancer Institute-designated Cancer Center and
expertise in drug discovery technologies. Sanford-Burnham is a nonprofit, independent
institute that employs 1,200 scientists and staff in San Diego (La Jolla), California, and
Orlando (Lake Nona), Florida. For more information, visit us at sanfordburnham.org.