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

• Type of Material: Article
• Authors: Paul M. Musille, Emory University; Manish Pathak, Emory University; Janelle L. Lauer, The Scripps Research Institute; William H. Hudson, Emory University; Patrick R. Griffin, The Scripps Research Institute; Eric Ortlund, Emory University
• Language: English
• Date: 2012-04-15
• Publisher: Nature Research (part of Springer Nature)
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2012, Rights Managed by Nature Publishing Group
• Final Published Version (URL): http://www.nature.com/nsmb/journal/v19/n5/full/nsmb.2279.html
• Title of Journal or Parent Work: Nature Structural and Molecular Biology
• ISSN: 1545-9993
• Volume: 19
• Issue: 5
• Start Page: 532
• End Page: S2
• Grant/Funding Information: 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: Diabetes; stem cells; nuclear receptor; phospholipids; NR5A; phosphatidylcholine
• Research Categories: Chemistry, Biochemistry; Biology, Molecular

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.