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

• Type of Material: Article
• Authors: Paul M. Musille, Emory University; Bradley R. Kossmann, Georgia State University; Jeffrey A. Kohn, Emory University; Ivaylo Ivanov, Georgia State University; Eric Ortlund, Emory University
• Language: English
• Date: 2016-01-15
• Publisher: American Society for Biochemistry and Molecular Biology
• Publication Version: Final Published Version
• Copyright Statement: © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.
• Final Published Version (URL): http://dx.doi.org/10.1074/jbc.M115.662874
• Title of Journal or Parent Work: Journal of Biological Chemistry
• Volume: 291
• Issue: 3
• Start Page: 1411
• End Page: 1426
• Grant/Funding Information: 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.; 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.).
• Keywords: phosphatidylcholine; allosteric regulation; nuclear receptor; Life Sciences & Biomedicine; molecular dynamics; Biochemistry & Molecular Biology; Science & Technology; diabetes; lipids
• Research Categories: Chemistry, Biochemistry

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.