DNA binding alters coactivator interaction surfaces of the intact VDR–RXR complex

Abstract

The vitamin D receptor (VDR) functions as an obligate heterodimer in complex with the retinoid X receptor (RXR). These nuclear receptors are multidomain proteins, and it is unclear how various domains interact with one another within the nuclear receptor heterodimer. Here, we show that binding of intact heterodimer to DNA alters the receptor dynamics in regions remote from the DNA-binding domains (DBDs), including the coactivator binding surfaces of both co-receptors, and that the sequence of the DNA response element can determine these dynamics. Furthermore, agonist binding to the heterodimer results in changes in the stability of the VDR DBD, indicating that the ligand itself may play a role in DNA recognition. These data suggest a mechanism by which nuclear receptors show promoter specificity and have differential effects on various target genes, providing insight into the function of selective nuclear receptor modulators.

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Figure 1: The interactions along the dimer interface of the RXR–VDR heterodimer.
Figure 2: Ligand-induced domain-domain interactions within the RXR–VDR heterodimer complex.
Figure 3: The interactions between RXR and VDR when they are bound to DNA.
Figure 4: Ligand dependency of SRC1 RID binding to the RXR–VDR heterodimer complex.

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Acknowledgements

We are grateful for support from M. Southern and S. Willis for software analyzing the HDX data. This work was supported in part by the Intramural Research Program of the US National Institutes of Health (NIH), National Institute of Mental Health (Grant U54-MH074404 to H. Rosen), the National Institute of General Medical Sciences (R01-GM084041 to P.R.G.), the National Institute of Diabetes and Digestive and Kidney Diseases (R01-DK080201to T.P.B.) and the James and Esther King Biomedical Research Program, Florida Department of Health (10KN-09 to D.J.K.).

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J.Z., M.J.C., K.R.S., J.A.D. and P.R.G. conceived of the project and designed the research; J.Z., L.L.B., Y.W., S.A.B., B.D.P., R.D.G.-O., J.B.B., M.A.I. and D.J.K. conducted the research; J.Z., M.J.C., K.R.S., L.L.B., Y.W., S.A.B., B.D.P., R.D.G.-O., J.B.B., M.A.I., D.J.K., T.P.B., J.A.D. and P.R.G. analyzed the data; and J.Z., K.R.S., T.P.B., S.A.B. and P.R.G. wrote the paper, with contributions from all authors.

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Correspondence to Patrick R Griffin.

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Zhang, J., Chalmers, M., Stayrook, K. et al. DNA binding alters coactivator interaction surfaces of the intact VDR–RXR complex. Nat Struct Mol Biol 18, 556–563 (2011). https://doi.org/10.1038/nsmb.2046

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