The signaling phospholipid PIP 3 creates a new interaction surface on the nuclear receptor SF-1
Copyright policy )The signaling phospholipid PIP 3 creates a new interaction surface on the nuclear receptor SF-1
Significance We previously reported that lipids PI(4,5)P 2 (PIP 2 ) and PI(3,4,5)P 3 (PIP 3 ) bind NR5A nuclear receptors to regulate their activity. Here, the crystal structures of PIP 2 and PIP 3 bound to NR5A1 (SF-1) define a new interaction surface that is organized by the solvent-exposed PIP n headgroups. We find that stabilization by the PIP 3 ligand propagates a signal that increases coactivator recruitment to SF-1, consistent with our earlier work showing that PIP 3 increases SF-1 activity. This newly created surface harbors a cluster of human mutations that lead to endocrine disorders, thus explaining how these puzzling mutations cripple SF-1 activity. We propose that this new surface acts as a PIP 3 -regulated interface between SF-1 and coregulatory proteins, analogous to the function of membrane-bound phosphoinositides.
- University of California, San Francisco United States
- SLAC National Accelerator Laboratory United States
- Joint Center for Structural Genomics United States
Models, Molecular, Surface Properties, Molecular Conformation, Mutation, Missense, Electrons, Steroidogenic Factor 1, Crystallography, X-Ray, Ligands, Phosphatidylinositols, ligand dependent, Mice, Models, Animals, Humans, Computer Simulation, Amino Acids, crystallography, Cell Nucleus, lipid transport, Chromatography, Crystallography, nucleus, Temperature, Molecular, Water, Biological Transport, Surface Plasmon Resonance, Lipids, Mutation, X-Ray, Solvents, Generic health relevance, Missense, transcription, Peptides, Signal Transduction
Models, Molecular, Surface Properties, Molecular Conformation, Mutation, Missense, Electrons, Steroidogenic Factor 1, Crystallography, X-Ray, Ligands, Phosphatidylinositols, ligand dependent, Mice, Models, Animals, Humans, Computer Simulation, Amino Acids, crystallography, Cell Nucleus, lipid transport, Chromatography, Crystallography, nucleus, Temperature, Molecular, Water, Biological Transport, Surface Plasmon Resonance, Lipids, Mutation, X-Ray, Solvents, Generic health relevance, Missense, transcription, Peptides, Signal Transduction
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