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An Allosteric Network in LRH‐1 Mediates Phospholipid‐Driven Gene Regulation
Author(s) -
Kohn Jeffrey,
Musille Paul,
Kossmann Bradley,
Ivanov Ivaylo,
Ortlund Eric
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.715.28
Subject(s) - allosteric regulation , coactivator , nuclear receptor , corepressor , transcription factor , ligand (biochemistry) , psychological repression , gene , chemistry , microbiology and biotechnology , binding site , biology , receptor , biochemistry , gene expression
The orphan nuclear receptor (NR) liver receptor homolog‐1 (LRH‐1) has been adopted after the discovery that phospholipids (PLs) could bind to its ligand binding pocket (LBP) and drive the regulation of many genes involved in metabolism, steroidogenesis, cell cycle, and the unfolded protein response. The transcription or repression of these genes is contingent upon the properties of the bound PL: mid‐chain phosphatidylcholines such as DLPC are LRH‐1 agonists and have antidiabetic effects, while long‐chain saturated PCs and PLs with other head groups do not, despite binding to LRH‐1. Like other NRs, LRH‐1 regulates genes via the recruitment of transcriptional coregulators. The PL bound to LRH‐1 dictates its preference for coactivators or corepressors. Using the combination of X‐ray crystallography and molecular dynamics, we have identified an allosteric network that connects the mouth of the LRH‐1 LBP to the AF‐2 coregulator binding surface via helices 3‐6, which traverse the LBP. Clustering analyses reveal that the molecular motions between these two areas become coordinated upon the binding of an activating PL, stabilizing the AF‐2 to favor coactivator binding. In the apo state, or when bound to nonactivating PLs, corepressor binding is favored. Ligand‐coregulator disagreement weakens this network, disfavoring the binding of a coregulator whose activation or repression state does not match that of the ligand. This network allows PLs to finely tune the expression of entire gene programs that control many aspects of cellular and metabolic activity, and may be exploitable by small molecule therapeutics for the treatment of human diseases, including metabolic disorders and cancer.