Diabetes-associated mutations in a beta-cell transcription factor destabilize an antiparallel "mini-zipper" in a dimerization interface

Maturity-onset diabetes of the young, a monogenic form of Type II diabetes mellitus, is most commonly caused by mutations in hepatic nuclear factor 1 alpha (HNF-1 alpha), Here, the dimerization motif of HNF-1 alpha is shown t o form an intermolecular four-helix bundle. One face contains an antiparall el coiled coil whereas the other contains splayed alpha-helices. The "mini- zipper" is complementary in structure and symmetry to the top surface of a transcriptional coactivator (dimerization cofactor of homeodomains). The bu ndle is destabilized by a subset of mutations associated with maturity-onse t diabetes of the young. Impaired dimerization of a beta-cell transcription factor thus provides a molecular mechanism of metabolic deregulation in di abetes mellitus.