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.

Benjah-bmm27 via Wikimedia Commons

A ribbon diagram of insulin as a hexamer stabilized by two zinc molecules with the coordinating histidine residues shown as sticks.

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.