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Structure and Dynamics of the Liver Receptor Homolog 1-PGC1α Complex
Suzanne G Mays1, C Denise Okafor1, Micheal L Tuntland1
1Department of Biochemistry, Emory University School of Medicine, Atlanta, Georgia (S.G.M., C.D.O., M.L.T., E.A.O.); School of Chemistry, University of Southampton, Southampton, United Kingdom (R.J.W., J.S.); and Department of Molecular Medicine, Scripps Research Institute, Jupiter, Florida (V.D., P.R.G.).
Molecular Pharmacology
|April 2, 2017
Summary
Peroxisome proliferator-activated gamma coactivator 1-alpha (PGC1α) binds liver receptor homolog 1 (LRH-1) via a charge clamp, inducing conformational changes that regulate energy metabolism. This interaction is stronger than with other coactivators, offering therapeutic targets.
Area of Science:
- Biochemistry
- Structural Biology
- Molecular Endocrinology
Background:
- Peroxisome proliferator-activated gamma coactivator 1-alpha (PGC1α) is a key regulator of cellular energy metabolism.
- Liver receptor homolog 1 (LRH-1) is an orphan nuclear receptor involved in glucose and lipid homeostasis.
- The interaction between PGC1α and LRH-1 is known to activate LRH-1, but the underlying mechanisms remain unclear.
Purpose of the Study:
- To elucidate the molecular mechanisms by which PGC1α modulates LRH-1 conformation and transcriptional activity.
- To characterize the structural basis of the LRH-1-PGC1α complex.
- To compare the coactivator activity of PGC1α with another coactivator, nuclear receptor coactivator-2 (Tif2).
Main Methods:
- Biochemical assays, including coregulator peptide recruitment assays.
- X-ray crystallography to determine the structure of the LRH-1-PGC1α complex.
- Molecular dynamics simulations to analyze conformational changes and signaling pathways.
Main Results:
- Purified LRH-1 bound PGC1α with higher affinity than Tif2.
- The crystal structure revealed hydrophobic contacts and a critical charge clamp at the LRH-1-PGC1α interface.
- PGC1α induced significant correlated atomic motion throughout the LRH-1 activation surface, dependent on the charge clamp.
- Tif2 induced weaker signaling at the activation surface but promoted allosteric signaling from a different region.
Conclusions:
- The PGC1α-LRH-1 interaction involves a charge clamp mechanism that drives conformational changes essential for LRH-1 transcriptional activation.
- PGC1α is a more potent activator of LRH-1 than Tif2.
- Understanding these mechanisms may lead to targeted therapies for metabolic diseases by modulating PGC1α-dependent LRH-1 signaling.