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Author Notes:

To whom correspondence should be addressed: Eric A. Ortlund, Department of Biochemistry, Emory University School of Medicine, Atlanta, GA 30322, USA. Telephone: (404) 727-5014. Fax: (404) 727-2738. Email: eric.ortlund@emory.edu.

P.M.M. purified, crystallized and determined both LRH-1 structures, measured phospholipid levels and carried out co-regulator-peptide interaction studies.

M.C.P. measured lipid phosphorus levels, optimized apo LRH-1 production and carried out co-regulator peptide interaction studies.

W.H.H. conducted reporter gene experiments.

J.L.L. and P.R.G. conducted thermal unfolding and HDX experiments.

P.M.M., J.L.L., P.R.G. and E.A.O. analyzed and interpreted the data.

P.M.M. and E.A.O. conceived the experiments and wrote the manuscript.

Paul M. Musille and Manish Pathak contributed equally.

We thank Dr. Nicholas T. Seyfried in the Dept. of Biochemistry at the Emory University for his help with acquiring the mass spectral data.

The authors declare no competing financial interests.

Subjects:

Research Funding:

This work was supported with start up funds from Emory University.

PMM was supported by Emory-NIEHS Graduate and Postdoctoral Training in Toxicology (T32ES012870).

Keywords:

  • nuclear receptor
  • stem cells
  • phospholipids
  • NR5A
  • Diabetes
  • phosphatidylcholine

Antidiabetic phospholipid–nuclear receptor complex reveals the mechanism for phospholipid-driven gene regulation

Tools:

Journal Title:

Nature Structural and Molecular Biology

Volume:

Volume 19, Number 5

Publisher:

, Pages 532-S2

Type of Work:

Article | Post-print: After Peer Review

Abstract:

The nuclear receptor Liver Receptor Homolog-1, LRH-1, plays an important role in controlling lipid and cholesterol homeostasis and is a potential target for treatment of diabetes and hepatic diseases. LRH-1 is known to bind phospholipids (PLs) but the role of PLs in controlling LRH-1 activation remains highly debated. Here we describe the structure of both apo LRH-1 and the protein in complex with the antidiabetic dilauroylphosphatidylcholine (DLPC). Our studies show that DLPC binding is a novel dynamic process that alters coregulator selectivity and that the lipid-free receptor interacts with widely expressed corepressors. These observations greatly enhance our understating of LRH-1 regulation and highlight its importance as a novel therapeutic target for controlling diabetes.

Copyright information:

© 2012, Rights Managed by Nature Publishing Group

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