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The Signaling Phospholipid PIP 3 Functions As a Ligand Hormone For Nuclear Receptors
Author(s) -
Ingraham Holly,
Blind Raymond,
Sablin Elena,
Das Debanu,
Fletterick Robert
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.493.3
Subject(s) - nuclear receptor , receptor , ligand (biochemistry) , microbiology and biotechnology , chemistry , biochemistry , nuclear pore , signal transduction , nuclear export signal , nuclear transport , transcription factor , biology , cell nucleus , cytoplasm , gene
The existence of nuclear, non‐membrane pools of signaling phosphoinositides (PIPs) was reported over two decades ago. Consistent with these early reports, lipid‐modifying enzymes responsible for phosphoinositide metabolism are found in the nucleus. How the lipid tails of nuclear phosphoinositides can exist in a non‐membrane environment is a major unresolved question. Our prior work showed that bacterial phospholipids bind to NR5A nuclear receptors (Krylova et al, Cell 2005); these transcription factors are important in regulating steroid and cholesterol homeostasis. Here, we report that the phosphoinositides PIP 2 and PIP 3 bind both hLRH‐1 (NR5A2) and hSF‐1 (NR5A1) with nM affinity. New X‐ray crystal structures of SF‐1 (2.4 Å) and LRH‐1 (1.8 Å) bound to PIP 3 reveal the lipid tails of PIP 3 nestled into the hydrophobic cavity with the headgroup solvent exposed and poised for modification by lipid kinases and phosphatases, as we previously reported (Blind et al, Sci Signaling 2012). As NR5A ligands, PIPs diverge chemically from other NR hormones in that they contain a hydrophilic as well as a long, extended hydrophobic moiety. Thus, our findings expand previously held notions of classic ligands and explain a puzzling cluster of human NR5A1 disease‐associated mutations found at the pocket entrance. These structures of PIP 3 anchored in proteins in a non‐membrane environment suggest that this high affinity phosphoinositide ligand stabilizes dynamic regions at the pocket entrance and acts as a regulatory ligand to enhance receptor functionality through a novel protein‐lipid interface.