How transcription factor mutations shape diabetes risk
Diabetes affects hundreds of millions of people worldwide. The disease features elevated blood glucose levels and disrupted fat and protein metabolism. The musculoaponeurotic fibrosarcoma, or MAF, family of transcription factors regulate various processes in tissue development, including hormone production in pancreatic islet cells. Within this family, MAFA and MAFB are essential for development and maturation of insulin- and glucagon-producing cells.
Previous research showed that MAFA and MAFB expression is affected in diabetes, both Type 1 and Type 2. In addition, a mutation in MAFA that prevents phosphorylation of a key serine residue causes monogenic diabetes. Mutation of the equivalent residue in MAFB leads to a pediatric multisystem disorder. In a recent Journal of Biological Chemistry article, Jeeyeon Cha, Xin Tong and Katie Coate from Vanderbilt University and collaborators in the U.S. examined how mutations in conserved DNA-binding domains of the MAF proteins impact their regulation of the insulin gene. The authors used targeted mutagenesis and artificial intelligence structure prediction using AlphaFold 2 for their analysis.
They found one MAFA variant, with a mutation in the conserved DNA-binding region, that exhibited normal activity. The equivalent mutation in MAFB did not retain normal activity. Therefore, the researchers searched for structural differences between the MAFA and MAFB proteins outside of the DNA-binding region that might also contribute to its activity. Their AlphaFold 2 models showed that the two proteins differed in the C-terminal domains. The researchers created chimeras by exchanging the two C-terminal domains of MAFA and MAFB, which changed how each protein regulated the insulin gene. These results help clarify differences between MAFA and MAFB, which of their domains affect activity and possible ways that they contribute to different disease states.
Future studies will focus on regions of MAFA and MAFB that may interact with other coregulators of the insulin gene.
Enjoy reading ASBMB Today?
Become a member to receive the print edition four times a year and the digital edition monthly.
Learn moreGet the latest from ASBMB Today
Enter your email address, and we’ll send you a weekly email with recent articles, interviews and more.
Latest in Science
Science highlights or most popular articles
The dual role of asprosin in chronic fatty liver disease
Researchers uncover a hormone called asprosin that may serve as a potential biomarker for the diagnosis of chronic fatty liver disease and monitoring disease progression.
Novel inhibitor targets RAS-driven cancers
Researchers in Louisville identify a small-molecule drug that blocks RALGEF signaling downstream of mutant RAS. The compound suppresses tumor growth with low toxicity, revealing a new therapeutic strategy for RAS-driven malignancies.
Catching tau in the act
Using a new proximity-labeling approach, researchers reveal how tangles of the brain-associated protein tau may disrupt RNA biology long before neurons die.
How copper delivery fuels bacterial respiration
Researchers identify the roles of several proteins in copper homeostasis in the aerobic bacterium Caulobacter vibrioides.
Revealing the glycoproteome of a cancer subtype
Researchers mapped the glycoproteome of extrahepatic cholangiocarcinoma and compared it to intrahepatic tumors. Differences in sugar modifications and immune cell content suggest new biomarkers and guide development of targeted immunotherapies.
Uncovering the mechanisms of a glycosylation disorder
Mutations in OGT, an enzyme that adds sugars to proteins, cause a rare neurological disorder. Using proteomics, researchers reveal how OGT interactions with TET proteins may trigger epigenetic changes and early neural defects.