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Structural basis of dimerization, coactivator recognition and MODY3 mutations in HNF-1alpha.
R B Rose1, J H Bayle, J A Endrizzi
1Department of Molecular and Cell Biology, University of California, Berkeley, California 94720-3206, USA.
Nature Structural Biology
|August 31, 2000
Summary
Mutations in hepatocyte nuclear factor-1alpha (HNF-1alpha) cause MODY3 diabetes. Structural and biochemical studies reveal how HNF-1alpha mutations disrupt its interaction with coactivator DCoH, leading to reduced activator function.
Area of Science:
- Molecular Biology
- Genetics
- Endocrinology
Background:
- Maturity-onset diabetes of the young type 3 (MODY3) is caused by mutations in the HNF-1alpha gene.
- MODY3 mutations often affect the HNF-1alpha dimerization domain (HNF-p1), crucial for binding the coactivator DCoH.
Purpose of the Study:
- To elucidate the structural basis of DCoH-HNF-1alpha interaction.
- To understand the molecular mechanisms by which MODY3 mutations in HNF-p1 impair transcriptional activation.
Main Methods:
- Cocrystallography of the DCoH-HNF-p1 complex.
- Biochemical characterization of MODY3 mutations in HNF-p1.
Main Results:
- The DCoH-HNF-p1 complex forms a unique dimer of dimers with HNF-p1 in a four-helix bundle.
- A bifunctional interface on DCoH mediates HNF-1alpha binding and DCoH homotetramer formation.
- MODY3 mutations in HNF-p1 were shown to impair activator function through two distinct mechanisms.
Conclusions:
- The study reveals the structural intricacies of the DCoH-HNF-1alpha complex.
- Understanding these mechanisms provides insight into MODY3 pathogenesis and potential therapeutic targets.