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

We previously reported that lipids PI(4,5)P2 (PIP2) and PI(3,4,5)P3 (PIP3) bind NR5A nuclear receptors to regulate their activity. Here, the crystal structures of PIP2 and PIP3 bound to NR5A1 (SF-1) define a new interaction surface that is organized by the solvent-exposed PIPn headgroups. We find that stabilization by the PIP3 ligand propagates a signal that increases coactivator recruitment to SF-1, consistent with our earlier work showing that PIP3 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. Finally, we propose that this new surface acts as a PIP3-regulated interface between SF-1 and coregulatory proteins, analogous to the function of membrane-bound phosphoinositides.
Authors:
 [1] ;  [2] ;  [2] ;  [3] ;  [3] ;  [3] ;  [2] ;  [1]
  1. Univ. of California, San Francisco, CA (United States). Dept. of Cellular and Molecular Pharmacology
  2. Univ. of California, San Francisco, CA (United States). Dept. of Biochemistry and Biophysics
  3. SLAC National Accelerator Lab., Menlo Park, CA (United States). Joint Center for Structural Genomics; SLAC National Accelerator Lab., Menlo Park, CA (United States). Stanford Synchrotron Radiation Lightsource (SSRL)
Publication Date:
OSTI Identifier:
1295339
Grant/Contract Number:
AC02-76SF00515; P41 GM103393; R01DK099722; R01DK072246; R01DK078075; W81XWH-12-1- 0396; U01 GM094614; GM094586
Type:
Accepted Manuscript
Journal Name:
Proceedings of the National Academy of Sciences of the United States of America
Additional Journal Information:
Journal Volume: 111; Journal Issue: 42; Journal ID: ISSN 0027-8424
Publisher:
National Academy of Sciences, Washington, DC (United States)
Research Org:
SLAC National Accelerator Laboratory (SLAC), Menlo Park, CA (United States)
Sponsoring Org:
USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22)
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES transcription; nucleus; crystallography; ligand dependent; lipid transport