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

Blind, Raymond D.; Sablin, Elena P.; Kuchenbecker, Kristopher M.; Chiu, Hsiu-Ju; Deacon, Ashley M.; Das, Debanu; Fletterick, Robert J.; Ingraham, Holly A.

doi:10.1073/pnas.1416740111

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

Journal Article · Mon Oct 06 00:00:00 EDT 2014 · Proceedings of the National Academy of Sciences of the United States of America

DOI:https://doi.org/10.1073/pnas.1416740111· OSTI ID:1295339

Blind, Raymond D. ^[1]; Sablin, Elena P. ^[2]; Kuchenbecker, Kristopher M. ^[2]; Chiu, Hsiu-Ju ^[3]; Deacon, Ashley M. ^[3]; Das, Debanu ^[3]; Fletterick, Robert J. ^[2]; Ingraham, Holly A. ^[1]

Univ. of California, San Francisco, CA (United States). Dept. of Cellular and Molecular Pharmacology
Univ. of California, San Francisco, CA (United States). Dept. of Biochemistry and Biophysics
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)

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.

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Research Organization:: SLAC National Accelerator Laboratory (SLAC), Menlo Park, CA (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES)

Grant/Contract Number:: AC02-76SF00515; P41 GM103393; R01DK099722; R01DK072246; R01DK078075; W81XWH-12-1- 0396; U01 GM094614; GM094586

OSTI ID:: 1295339

Journal Information:: Proceedings of the National Academy of Sciences of the United States of America, Vol. 111, Issue 42; ISSN 0027-8424

Publisher:: National Academy of Sciences, Washington, DC (United States)Copyright Statement

Country of Publication:: United States

Language:: English

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Cited by: 48 works

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SF-1 expression in the hypothalamus is required for beneficial metabolic effects of exercise Fujikawa, Teppei; Castorena, Carlos M.; Pearson, Mackenzie eLife, Vol. 5 https://doi.org/10.7554/elife.18206	journal	November 2016
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LRH-1 regulates hepatic lipid homeostasis and maintains arachidonoyl phospholipid pools critical for phospholipid diversity Miranda, Diego A.; Krause, William C.; Cazenave-Gassiot, Amaury JCI Insight, Vol. 3, Issue 5 https://doi.org/10.1172/jci.insight.96151	journal	March 2018
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Title: The signaling phospholipid PIP3 creates a new interaction surface on the nuclear receptor SF-1

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Cited By (17)

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