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

Paul M Musille1, Manish Pathak1, Janelle L Lauer2

  • 1Department of Biochemistry, Emory University School of Medicine, Atlanta, GA 30322, USA.

Nature Structural & Molecular Biology
|April 17, 2012
PubMed

Insights

The liver receptor homolog-1 (LRH-1) protein

Area of Science:

  • Biochemistry and molecular biology
  • Endocrinology
  • Metabolic diseases

Background:

  • The nuclear receptor liver receptor homolog-1 (LRH-1) plays a key role in regulating lipid and cholesterol metabolism.
  • LRH-1 is a potential therapeutic target for diabetes and liver diseases.
  • The precise role of phospholipids in LRH-1 activation is not fully understood.

Purpose of the Study:

  • To elucidate the structural and dynamic mechanisms of LRH-1 activation by phospholipids.
  • To investigate the interaction between LRH-1 and the antidiabetic phospholipid dilauroylphosphatidylcholine (DLPC).

Main Methods:

  • X-ray crystallography to determine the structures of apo LRH-1 and LRH-1-DLPC complex.
  • Hydrogen-deuterium exchange mass spectrometry (HDX-MS) to study protein dynamics.
  • Functional assays to assess co-regulator binding and activity.

Main Results:

  • The crystal structure of LRH-1 in complex with DLPC was determined.
  • DLPC binding was shown to be a dynamic process that modulates LRH-1 conformation.
  • Lipid-free LRH-1 exhibits structural fluctuations enabling interaction with co-repressors.
  • DLPC binding alters co-regulator selectivity, favoring co-activators.

Conclusions:

  • Phospholipid binding, specifically DLPC, is crucial for regulating LRH-1 activity and co-regulator interaction.
  • Understanding LRH-1's dynamic structural changes upon lipid binding provides new insights into its role in metabolic homeostasis.
  • These findings reinforce LRH-1 as a promising therapeutic target for managing diabetes and related hepatic conditions.

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