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Structural basis of dimerization, coactivator recognition and MODY3 mutations in HNF-1alpha.

Rose RB, Bayle JH, Endrizzi JA, Cronk JD, Crabtree GR, Alber T
Nat Struct Biol 7 744-8 (2000)
Related entries: 1dch, 1dco, 1dcp

Cited: 27 times
EuropePMC logo PMID: 10966642

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.

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Related citations provided by authors (2)

  1. Crystal structure of DCoH, a bifunctional, protein-binding transcriptional coactivator.. Endrizzi JA, Cronk JD, Wang W, Crabtree GR, Alber T Science 268 556-9 (1995)
  2. High-resolution structures of the bifunctional enzyme and transcriptional coactivator DCoH and its complex with a product analogue.. Cronk JD, Endrizzi JA, Alber T Protein Sci 5 1963-72 (1996)

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