Diabetes-associated mutations in a β-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 1α (HNF-1α). Here, the dimerization motif of HNF-1α is shown to form an intermolecular four-helix bundle. One face contains an antiparallel coiled coil whereas the other contains splayed α-helices. The “mini-zipper” is complementary in structure and symmetry to the top surface of a transcriptional coactivator (dimerization cofactor of homeodomains). The bundle is destabilized by a subset of mutations associated with maturity-onset diabetes of the young. Impaired dimerization of a β-cell transcription factor thus provides a molecular mechanism of metabolic deregulation in diabetes mellitus.