Structural basis of dimerization, coactivator recognition and MODY3 mutations in HNF-1alpha.
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Rose RB, Bayle JH, Endrizzi JA, Cronk JD, Crabtree GR, Alber T
Structural basis of dimerization, coactivator recognition and MODY3 mutations in HNF-1alpha.
Nat Struct Biol. 2000 Sep;7(9):744-8.
- PubMed ID
- 10966642 [ View in PubMed]
- Abstract
Maturity-onset diabetes of the young type 3 (MODY3) results from mutations in the transcriptional activator hepatocyte nuclear factor-1alpha (HNF-1alpha). Several MODY3 mutations target the HNF-1alpha dimerization domain (HNF-p1), which binds the coactivator, dimerization cofactor of HNF-1 (DCoH). To define the mechanism of coactivator recognition and the basis for the MODY3 phenotype, we determined the cocrystal structure of the DCoH-HNF-p1 complex and characterized biochemically the effects of MODY3 mutations in HNF-p1. The DCoH-HNF-p1 complex comprises a dimer of dimers in which HNF-p1 forms a unique four-helix bundle. Through rearrangements of interfacial side chains, a single, bifunctional interface in the DCoH dimer mediates both HNF-1alpha binding and formation of a competing, transcriptionally inactive DCoH homotetramer. Consistent with the structure, MODY3 mutations in HNF-p1 reduce activator function by two distinct mechanisms.