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Author Notes:

To whom correspondence should be addressed: Eric Ortlund. Tel.: 404-727-5014; Fax: 404-727-2738; E-mail: eortlun@emory.edu.

P. M. M., B. R. K., J. A. K., I. I., and E. A. O. participated in research design.

P. M.M., B. R. K., and J. A. K. conducted the experiments.

P. M. M., B. R. K., J. A. K., I. I., and E. A. O. performed data analysis.

P. M. M., B. R. K., J. A. K., I. I., and E. A. O. wrote or contributed to the writing of the manuscript.

The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

The atomic coordinates and structure factors (codes 4PLD and 4PLE) have been deposited in the Protein Data Bank (http://wwpdb.org/).

Subject:

Research Funding:

This work was supported by National Institutes of Health Grant RO1DK095750 from NIDDK (to E. A. O.), Grant R01GM110387 from NIGMS (to I. I.), and Emory-NIEHS Graduate and Postdoctoral Training in Toxicology Grant T32ES012870 (to P. M. M.), American Heart Association Predoctoral Grant 12PRE12060583, National Science Foundation CAREER Award MCB-1149521, and a Molecular Basis Diseases fellowship (to B. R. K.).

Computational resources were provided in part by National Science Foundation XSEDE Allocation CHE110042 and Allocation m1254 at the National Energy Research Scientific Computing Center supported by the United States Department of Energy Office of Science Contract DE-AC02-05CH11231.

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Biochemistry & Molecular Biology
  • allosteric regulation
  • diabetes
  • molecular dynamics
  • nuclear receptor
  • phosphatidylcholine
  • lipids

Unexpected Allosteric Network Contributes to LRH-1 Co-regulator Selectivity

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Journal Title:

Journal of Biological Chemistry

Volume:

Volume 291, Number 3

Publisher:

, Pages 1411-1426

Type of Work:

Article | Final Publisher PDF

Abstract:

Phospholipids (PLs) are unusual signaling hormones sensed by the nuclear receptor liver receptor homolog-1 (LRH-1), which has evolved a novel allosteric pathway to support appropriate interaction with co-regulators depending on ligand status. LRH-1 plays an important role in controlling lipid and cholesterol homeostasis and is a potential target for the treatment of metabolic and neoplastic diseases. Although the prospect of modulating LRH-1 via small molecules is exciting, the molecular mechanism linking PL structure to transcriptional co-regulator preference is unknown. Previous studies showed that binding to an activating PL ligand, such as dilauroylphosphatidylcholine, favors LRH-1's interaction with transcriptional coactivators to up-regulate gene expression. Both crystallographic and solution-based structural studies showed that dilauroylphosphatidylcholine binding drives unanticipated structural fluctuations outside of the canonical activation surface in an alternate activation function (AF) region, encompassing the β-sheet-H6 region of the protein. However, the mechanism by which dynamics in the alternate AF influences co-regulator selectivity remains elusive. Here, we pair x-ray crystallography with molecular modeling to identify an unexpected allosteric network that traverses the protein ligand binding pocket and links these two elements to dictate selectivity. We show that communication between the alternate AF region and classical AF2 is correlated with the strength of the co-regulator interaction. This work offers the first glimpse into the conformational dynamics that drive this unusual PL-mediated nuclear hormone receptor activation.

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© 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

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