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

Abstract

Maturity-onset diabetes of the young type 3 (MODY3) results from mutations in the transcriptional activator hepatocyte nuclear factor-1α (HNF-1α). Several MODY3 mutations target the HNF-1α 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-1α 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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Figure 1: Stereo view of the experimental, MAD-phased 2.6 Å resolution, electron density map contoured at 1 σ superimposed on the refined model.
Figure 2: Structure of the DCoH–HNF-p1 complex.
Figure 3: Bifunctional recognition surface of DCoH supports a model for autoinhibition of coactivator function.
Figure 4: Effects of MODY3 mutations in the HNF-1α dimerization domain.

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Acknowledgements

We thank D.S. King for peptide synthesis and mass spectrometry. Data were collected at the Stanford Synchrotron Radiation Laboratory (SSRL) with the help of H. Bellamy. SSRL is operated by the Department of Energy, Office of Basic Energy Sciences. The SSRL Biotechnology Program is supported by the NIH National Center for Research Resources. R.B.R. was supported by postdoctoral fellowships from the NIH and the Juvenile Diabetes Foundation International. This research was supported by a grant from the NIH (T.A.).

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Correspondence to Tom Alber.

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