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

ABSTRACT: Maturity-onset diabetes of the young, a monogenic form of Type II diabetes mellitus, is most commonly caused by mutations in hepatic nuclear factor 1alpha (HNF-1alpha). Here, the dimerization motif of HNF-1alpha is shown to form an intermolecular four-helix bundle. One face contains an antiparallel 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 bundle is destabilized by a subset of mutations associated with maturity-onset diabetes of the young. Impaired dimerization of a beta-cell transcription factor thus provides a molecular mechanism of metabolic deregulation in diabetes mellitus.

SUBMITTER: Hua QX

PROVIDER: S-EPMC15743 | biostudies-literature | 2000 Feb

REPOSITORIES: biostudies-literature

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

Hua Q X QX Zhao M M Narayana N N Nakagawa S H SH Jia W W Weiss M A MA

Proceedings of the National Academy of Sciences of the United States of America 20000201 5

Maturity-onset diabetes of the young, a monogenic form of Type II diabetes mellitus, is most commonly caused by mutations in hepatic nuclear factor 1alpha (HNF-1alpha). Here, the dimerization motif of HNF-1alpha is shown to form an intermolecular four-helix bundle. One face contains an antiparallel 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 ...[more]

PMID: 10696112

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