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

Jun Zhang; Michael J. Chalmers; Keith R. Stayrook; Lorri L. Burris; Yongjun Wang; Scott A. Busby; Bruce D. Pascal; Ruben D. Garcia-Ordonez; John B. Bruning; Monica A. Istrate; Douglas J. Kojetin; Jeffrey A. Dodge; Thomas P. Burris; Patrick R. Griffin

doi:10.1038/nsmb.2046

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

Jun Zhang, Michael J. Chalmers, Keith R. Stayrook, Lorri L. Burris, Yongjun Wang, Scott A. Busby, Bruce D. Pascal, Ruben D. Garcia-Ordonez, John B. Bruning, Monica A. Istrate, Douglas J. Kojetin, Jeffrey A. Dodge, Thomas P. Burris, Patrick R. Griffin

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171 Scopus citations

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.

Original language	English (US)
Pages (from-to)	556-563
Number of pages	8
Journal	Nature Structural and Molecular Biology
Volume	18
Issue number	5
DOIs	https://doi.org/10.1038/nsmb.2046
State	Published - May 2011
Externally published	Yes

ASJC Scopus subject areas

Structural Biology
Molecular Biology

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Zhang, J., Chalmers, M. J., Stayrook, K. R., Burris, L. L., Wang, Y., Busby, S. A., Pascal, B. D., Garcia-Ordonez, R. D., Bruning, J. B., Istrate, M. A., Kojetin, D. J., Dodge, J. A., Burris, T. P., & Griffin, P. R. (2011). DNA binding alters coactivator interaction surfaces of the intact VDR-RXR complex. Nature Structural and Molecular Biology, 18(5), 556-563. https://doi.org/10.1038/nsmb.2046

Zhang, J, Chalmers, MJ, Stayrook, KR, Burris, LL, Wang, Y, Busby, SA, Pascal, BD, Garcia-Ordonez, RD, Bruning, JB, Istrate, MA, Kojetin, DJ, Dodge, JA, Burris, TP & Griffin, PR 2011, 'DNA binding alters coactivator interaction surfaces of the intact VDR-RXR complex', Nature Structural and Molecular Biology, vol. 18, no. 5, pp. 556-563. https://doi.org/10.1038/nsmb.2046

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title = "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.",

author = "Jun Zhang and Chalmers, {Michael J.} and Stayrook, {Keith R.} and Burris, {Lorri L.} and Yongjun Wang and Busby, {Scott A.} and Pascal, {Bruce D.} and Garcia-Ordonez, {Ruben D.} and Bruning, {John B.} and Istrate, {Monica A.} and Kojetin, {Douglas J.} and Dodge, {Jeffrey A.} and Burris, {Thomas P.} and Griffin, {Patrick R.}",

note = "Funding Information: 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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AU - Wang, Yongjun

AU - Busby, Scott A.

AU - Pascal, Bruce D.

AU - Garcia-Ordonez, Ruben D.

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AU - Istrate, Monica A.

AU - Kojetin, Douglas J.

AU - Dodge, Jeffrey A.

AU - Burris, Thomas P.

AU - Griffin, Patrick R.

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N2 - 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.

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

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