Structural analyses reveal phosphatidyl inositols as ligands for the NR5 orphan receptors SF-1 and LRH-1

Irina N. Krylova; Elena P. Sablin; Jamie Moore; Robert X. Xu; Gregory M. Waitt; J. Andrew MacKay; Dalia Juzumiene; Jane M. Bynum; Kevin Madauss; Valerie Montana; Lioudmila Lebedeva; Miyuki Suzawa; Jon D. Williams; Shawn P. Williams; Rodney K. Guy; Joseph W. Thornton; Robert J. Fletterick; Timothy M. Willson; Holly A. Ingraham

doi:10.1016/j.cell.2005.01.024

Structural analyses reveal phosphatidyl inositols as ligands for the NR5 orphan receptors SF-1 and LRH-1

Irina N. Krylova, Elena P. Sablin, Jamie Moore, Robert X. Xu, Gregory M. Waitt, J. Andrew MacKay, Dalia Juzumiene, Jane M. Bynum, Kevin Madauss, Valerie Montana, Lioudmila Lebedeva, Miyuki Suzawa, Jon D. Williams, Shawn P. Williams, Rodney K. Guy, Joseph W. Thornton, Robert J. Fletterick, Timothy M. Willson, Holly A. Ingraham

Research output: Contribution to journal › Article › peer-review

354 Scopus citations

Abstract

Vertebrate members of the nuclear receptor NR5A subfamily, which includes steroidogenic factor 1 (SF-1) and liver receptor homolog 1 (LRH-1), regulate crucial aspects of development, endocrine homeostasis, and metabolism. Mouse LRH-1 is believed to be a ligand-independent transcription factor with a large and empty hydrophobic pocket. Here we present structural and biochemical data for three other NR5A members - mouse and human SF-1 and human LRH-1 - which reveal that these receptors bind phosphatidyl inositol second messengers and that ligand binding is required for maximal activity. Evolutionary analysis of structure-function relationships across the SF-1/LRH-1 subfamily indicates that ligand binding is the ancestral state of NR5A receptors and was uniquely diminished or altered in the rodent LRH-1 lineage. We propose that phospholipids regulate gene expression by directly binding to NR5A nuclear receptors.

Original language	English
Pages (from-to)	343-355
Number of pages	13
Journal	Cell
Volume	120
Issue number	3
DOIs	https://doi.org/10.1016/j.cell.2005.01.024
State	Published - Feb 11 2005

Bibliographical note

Funding Information:
We would like to thank Drs. D. Julius, K. Shokat, D. Stokoe, S. Wadekar, N. Jouravel, D. Moore, and F. Szoka for critical comments, experimental suggestions, and reagents. The IMCA-CAT beamline 17-ID (or 17-BM) at the Advanced Photon Source was supported by the companies of the Industrial Macromolecular Crystallography Association through a contract with Illinois Institute of Technology. We would like to thank Drs. Cheng Yang and Joseph Ferrara from Rigaku/MSC Inc. for an invitation to this facility. This work was funded by NIH 1R21-GM70792-1 and the Oregon Medical Research Foundation to J.W.T., a HHMI predoctoral fellowship to J.A.M., and a NIDDK-PO1 support to R.J.F., R.K.G., and H.A.I.

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1016/j.cell.2005.01.024

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Krylova, I. N., Sablin, E. P., Moore, J., Xu, R. X., Waitt, G. M., MacKay, J. A., Juzumiene, D., Bynum, J. M., Madauss, K., Montana, V., Lebedeva, L., Suzawa, M., Williams, J. D., Williams, S. P., Guy, R. K., Thornton, J. W., Fletterick, R. J., Willson, T. M., & Ingraham, H. A. (2005). Structural analyses reveal phosphatidyl inositols as ligands for the NR5 orphan receptors SF-1 and LRH-1. Cell, 120(3), 343-355. https://doi.org/10.1016/j.cell.2005.01.024

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title = "Structural analyses reveal phosphatidyl inositols as ligands for the NR5 orphan receptors SF-1 and LRH-1",

abstract = "Vertebrate members of the nuclear receptor NR5A subfamily, which includes steroidogenic factor 1 (SF-1) and liver receptor homolog 1 (LRH-1), regulate crucial aspects of development, endocrine homeostasis, and metabolism. Mouse LRH-1 is believed to be a ligand-independent transcription factor with a large and empty hydrophobic pocket. Here we present structural and biochemical data for three other NR5A members - mouse and human SF-1 and human LRH-1 - which reveal that these receptors bind phosphatidyl inositol second messengers and that ligand binding is required for maximal activity. Evolutionary analysis of structure-function relationships across the SF-1/LRH-1 subfamily indicates that ligand binding is the ancestral state of NR5A receptors and was uniquely diminished or altered in the rodent LRH-1 lineage. We propose that phospholipids regulate gene expression by directly binding to NR5A nuclear receptors.",

author = "Krylova, {Irina N.} and Sablin, {Elena P.} and Jamie Moore and Xu, {Robert X.} and Waitt, {Gregory M.} and MacKay, {J. Andrew} and Dalia Juzumiene and Bynum, {Jane M.} and Kevin Madauss and Valerie Montana and Lioudmila Lebedeva and Miyuki Suzawa and Williams, {Jon D.} and Williams, {Shawn P.} and Guy, {Rodney K.} and Thornton, {Joseph W.} and Fletterick, {Robert J.} and Willson, {Timothy M.} and Ingraham, {Holly A.}",

note = "Funding Information: We would like to thank Drs. D. Julius, K. Shokat, D. Stokoe, S. Wadekar, N. Jouravel, D. Moore, and F. Szoka for critical comments, experimental suggestions, and reagents. The IMCA-CAT beamline 17-ID (or 17-BM) at the Advanced Photon Source was supported by the companies of the Industrial Macromolecular Crystallography Association through a contract with Illinois Institute of Technology. We would like to thank Drs. Cheng Yang and Joseph Ferrara from Rigaku/MSC Inc. for an invitation to this facility. This work was funded by NIH 1R21-GM70792-1 and the Oregon Medical Research Foundation to J.W.T., a HHMI predoctoral fellowship to J.A.M., and a NIDDK-PO1 support to R.J.F., R.K.G., and H.A.I. ",

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Krylova, IN, Sablin, EP, Moore, J, Xu, RX, Waitt, GM, MacKay, JA, Juzumiene, D, Bynum, JM, Madauss, K, Montana, V, Lebedeva, L, Suzawa, M, Williams, JD, Williams, SP, Guy, RK, Thornton, JW, Fletterick, RJ, Willson, TM & Ingraham, HA 2005, 'Structural analyses reveal phosphatidyl inositols as ligands for the NR5 orphan receptors SF-1 and LRH-1', Cell, vol. 120, no. 3, pp. 343-355. https://doi.org/10.1016/j.cell.2005.01.024

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T1 - Structural analyses reveal phosphatidyl inositols as ligands for the NR5 orphan receptors SF-1 and LRH-1

AU - Krylova, Irina N.

AU - Sablin, Elena P.

AU - Moore, Jamie

AU - Xu, Robert X.

AU - Waitt, Gregory M.

AU - MacKay, J. Andrew

AU - Juzumiene, Dalia

AU - Bynum, Jane M.

AU - Madauss, Kevin

AU - Montana, Valerie

AU - Lebedeva, Lioudmila

AU - Suzawa, Miyuki

AU - Williams, Jon D.

AU - Williams, Shawn P.

AU - Guy, Rodney K.

AU - Thornton, Joseph W.

AU - Fletterick, Robert J.

AU - Willson, Timothy M.

AU - Ingraham, Holly A.

N1 - Funding Information: We would like to thank Drs. D. Julius, K. Shokat, D. Stokoe, S. Wadekar, N. Jouravel, D. Moore, and F. Szoka for critical comments, experimental suggestions, and reagents. The IMCA-CAT beamline 17-ID (or 17-BM) at the Advanced Photon Source was supported by the companies of the Industrial Macromolecular Crystallography Association through a contract with Illinois Institute of Technology. We would like to thank Drs. Cheng Yang and Joseph Ferrara from Rigaku/MSC Inc. for an invitation to this facility. This work was funded by NIH 1R21-GM70792-1 and the Oregon Medical Research Foundation to J.W.T., a HHMI predoctoral fellowship to J.A.M., and a NIDDK-PO1 support to R.J.F., R.K.G., and H.A.I.

PY - 2005/2/11

Y1 - 2005/2/11

N2 - Vertebrate members of the nuclear receptor NR5A subfamily, which includes steroidogenic factor 1 (SF-1) and liver receptor homolog 1 (LRH-1), regulate crucial aspects of development, endocrine homeostasis, and metabolism. Mouse LRH-1 is believed to be a ligand-independent transcription factor with a large and empty hydrophobic pocket. Here we present structural and biochemical data for three other NR5A members - mouse and human SF-1 and human LRH-1 - which reveal that these receptors bind phosphatidyl inositol second messengers and that ligand binding is required for maximal activity. Evolutionary analysis of structure-function relationships across the SF-1/LRH-1 subfamily indicates that ligand binding is the ancestral state of NR5A receptors and was uniquely diminished or altered in the rodent LRH-1 lineage. We propose that phospholipids regulate gene expression by directly binding to NR5A nuclear receptors.

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Structural analyses reveal phosphatidyl inositols as ligands for the NR5 orphan receptors SF-1 and LRH-1

Abstract

Bibliographical note

ASJC Scopus subject areas

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