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Proc Natl Acad Sci U S A. 2014 Oct 21;111(42):15054-9. doi: 10.1073/pnas.1416740111. Epub 2014 Oct 6.

The signaling phospholipid PIP3 creates a new interaction surface on the nuclear receptor SF-1.

Author information

1
Departments of Cellular and Molecular Pharmacology and.
2
Biochemistry and Biophysics, University of California, San Francisco, CA 94158; and.
3
Joint Center for Structural Genomics and Stanford Synchrotron Radiation Lightsource, SLAC National Accelerator Laboratory, Menlo Park, CA 94025.
4
Biochemistry and Biophysics, University of California, San Francisco, CA 94158; and robert.fletterick@ucsf.edu holly.ingraham@ucsf.edu.
5
Departments of Cellular and Molecular Pharmacology and robert.fletterick@ucsf.edu holly.ingraham@ucsf.edu.

Abstract

The signaling phosphatidylinositol lipids PI(4,5)P2 (PIP2) and PI(3,4,5)P3 (PIP3) bind nuclear receptor 5A family (NR5As), but their regulatory mechanisms remain unknown. Here, the crystal structures of human NR5A1 (steroidogenic factor-1, SF-1) ligand binding domain (LBD) bound to PIP2 and PIP3 show the lipid hydrophobic tails sequestered in the hormone pocket, as predicted. However, unlike classic nuclear receptor hormones, the phosphoinositide head groups are fully solvent-exposed and complete the LBD fold by organizing the receptor architecture at the hormone pocket entrance. The highest affinity phosphoinositide ligand PIP3 stabilizes the coactivator binding groove and increases coactivator peptide recruitment. This receptor-ligand topology defines a previously unidentified regulatory protein-lipid surface on SF-1 with the phosphoinositide head group at its nexus and poised to interact with other proteins. This surface on SF-1 coincides with the predicted binding site of the corepressor DAX-1 (dosage-sensitive sex reversal, adrenal hypoplasia critical region on chromosome X), and importantly harbors missense mutations associated with human endocrine disorders. Our data provide the structural basis for this poorly understood cluster of human SF-1 mutations and demonstrates how signaling phosphoinositides function as regulatory ligands for NR5As.

KEYWORDS:

crystallography; ligand dependent; lipid transport; nucleus; transcription

PMID:
25288771
PMCID:
PMC4210282
DOI:
10.1073/pnas.1416740111
[Indexed for MEDLINE]
Free PMC Article

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