4IS8

Divergent sequence tunes ligand sensitivity in phospholipid-regulated hormone receptors

Summary for 4IS8

• Entry DOI: 10.2210/pdb4is8/pdb
• Descriptor: Nuclear receptor subfamily 5 group A member 2 (2 entities in total)
• Functional Keywords: ligand binding domain, transcription
• Biological source: Homo sapiens (human)
• Cellular location: Nucleus (Probable): O00482
• Total number of polymer chains: 2
• Total formula weight: 55690.27

Authors

Musille, P.M.,Pathak, M.C.,Ortlund, E.A. (deposition date: 2013-01-16, release date: 2013-06-12, Last modification date: 2024-02-28)

Primary citation

Musille, P.M.,Pathak, M.,Lauer, J.L.,Griffin, P.R.,Ortlund, E.A.
Divergent Sequence Tunes Ligand Sensitivity in Phospholipid-regulated Hormone Receptors.
J.Biol.Chem., 288:20702-20712, 2013

PubMed Abstract: The members of the NR5A subfamily of nuclear receptors (NRs) are important regulators of pluripotency, lipid and glucose homeostasis, and steroidogenesis. Liver receptor homologue 1 (LRH-1; NR5A2) and steroidogenic factor 1 (SF-1; NR5A1) have therapeutic potential for the treatment of metabolic and neoplastic disease; however, a poor understanding of their ligand regulation has hampered the pursuit of these proteins as pharmaceutical targets. In this study, we dissect how sequence variation among LRH-1 orthologs affects phospholipid (PL) binding and regulation. Both human LRH-1 (hLRH-1) and mouse LRH-1 (mLRH-1) respond to newly discovered medium chain PL agonists to modulate lipid and glucose homeostasis. These PLs activate hLRH-1 by altering receptor dynamics in a newly identified alternate activation function region. Mouse and Drosophila orthologs contain divergent sequences in this region potentially altering PL-driven activation. Structural evidence suggests that these sequence differences in mLRH-1 and Drosophila FTZ-f1 (dmFTZ-f1) confer at least partial ligand independence, making them poor models for hLRH-1 studies; however, the mechanisms of ligand independence remain untested. We show using structural and biochemical methods that the recent evolutionary divergence of the mLRH-1 stabilizes the active conformation in the absence of ligand, yet does not abrogate PL-dependent activation. We also show by mass spectrometry and biochemical assays that FTZ-f1 is incapable of PL binding. This work provides a structural mechanism for the differential tuning of PL sensitivity in NR5A orthologs and supports the use of mice as viable therapeutic models for LRH-1-dependent diseases.

PubMed: 23737522
DOI: 10.1074/jbc.M113.472837

Experimental method

X-RAY DIFFRACTION (2.78 Å)