PIs as Ligands?

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Science  25 Feb 2005:
Vol. 307, Issue 5713, pp. 1173
DOI: 10.1126/science.307.5713.1173c

Phosphatidylinositol (PI) lipids are implicated in a broad range of processes, from the organization of signaling pathways to vesicle trafficking and control of the actin cytoskeleton. Krylova et al. suggest that these lipids may also serve as activating ligands for a class of orphan (so called because no regulatory ligand was known) nuclear receptors. The authors solved crystal structures of three nuclear receptor 5A family members: mouse mSF-1 and the human proteins hSF-1 and hLRH-1. Residual electron density in the ligand-binding pockets revealed that the crystallized proteins (expressed in and purified from bacteria) contained lipids. Testing with eukaryotic lipids revealed preferential binding to phosphatidylinositol 3,5-bisphosphate [PI(3,5)P2] and phosphatidylinositol 3,4,5-trisphosphate [PI(3,4,5)P3]. Although biological regulation by such lipids remains to be explored, mutant proteins designed to disrupt lipid binding showed decreased transcriptional activity. The mouse receptor appears to have lost ligand-binding activity, and phylogenetic analysis favors the scenario in which the ancestral nuclear receptor did bind lipids and this capacity was later lost in the rodent lineage. — LBR

Cell 120, 343 (2005).

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