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Divergent sequence tunes ligand sensitivity in phospholipid-regulated hormone receptors

Academic Article
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Overview

authors

  • Musille, P. M.
  • Pathak, M.
  • Lauer, J. L.
  • Griffin, Patrick
  • Ortlund, E. A.

publication date

  • July 2013

journal

  • Journal of Biological Chemistry  Journal

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.

subject areas

  • Amino Acid Sequence
  • Animals
  • Binding Sites
  • Crystallography, X-Ray
  • DNA-Binding Proteins
  • Drosophila Proteins
  • Drosophila melanogaster
  • Genetic Variation
  • Humans
  • Ligands
  • Mass Spectrometry
  • Mice
  • Models, Molecular
  • Molecular Sequence Data
  • Phosphatidylglycerols
  • Phospholipids
  • Protein Binding
  • Protein Structure, Tertiary
  • Receptors, Cytoplasmic and Nuclear
  • Recombinant Proteins
  • Sequence Homology, Amino Acid
  • Species Specificity
  • Transcription Factors
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Identity

PubMed Central ID

  • PMC3711333

International Standard Serial Number (ISSN)

  • 0021-9258

Digital Object Identifier (DOI)

  • 10.1074/jbc.M113.472837

PubMed ID

  • 23737522
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Additional Document Info

start page

  • 20702

end page

  • 20712

volume

  • 288

issue

  • 28

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