Structural Studies of HNF 1alpha and HNF 4alpha

A network of transcription factors controls the proper development and normal function of beta-cells, and inherited rrutations on the genes encoding some of these transcription factors cause monogenic dominant forms of diabetes known as maturity-onset diabetes of the young (MODY). Mutations m HNF1 alli\a and HNF4alphaare the most common causes of MODY, and the recent studies have revealed that HNF1 alpha and HNF4alpha are the master requlators of beta-cells directly afecting their physiology. 'M1ile the generation of large number of functional beta-cells from embryonic or tissue-specific stem/progenitor cells to replace the damaged or ill-devalopedbeta-cells seems to be a formidable task, targeting these transcription factors to help generate beta-cells or to enhance the function of existing beta-cells could make it more attainable These gene-specific transcription factors Initiate transcription by recognizing promoter regions of the target genes, interacting with other transcription factors for synergistic enhancement, and mediating additional interactions with coregulators to recruit the remainder of the main transcriptional rnachineg. However, detailed structural information on how the molecular interactions occur during the multi-complex formation and how they are disrupted by MOOY mutations is lacking. Thereore, we propose to solve the crystal structures of higher-order complexes made by HNF1alpha (Aim 1) and HNF4alpha (Aim 2). These structures should be valuable In understanding the tan scription regulatory mechanisms by HNF1alpha and HNF4alpha in beta-cells, and rational targeting of these transcription factors in order to modulate their activities.promote regeneration of beta-cells, boost survival and function, and reverse the adverse effects by the mutations, thus potential treatments for various forms of diabetes