Many ion channels are regulated by lipids1,2,3, but prominent motifs for lipid binding have not been identified in most ion channels. Recently, we reported that phospholipase Cγ1 (PLC-γ1) binds to and regulates TRPC3 channels4, components of agonist-induced Ca2+ entry into cells. This interaction requires a domain in PLC-γ1 that includes a partial pleckstrin homology (PH) domain—a consensus lipid-binding and protein-binding sequence5,6. We have developed a gestalt algorithm to detect hitherto ‘invisible’ PH and PH-like domains, and now report that the partial PH domain of PLC-γ1 interacts with a complementary partial PH-like domain in TRPC3 to elicit lipid binding and cell-surface expression of TRPC3. Our findings imply a far greater abundance of PH domains than previously appreciated, and suggest that intermolecular PH-like domains represent a widespread signalling mode.
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We thank D. Boehning, G. Caraveo, J. Kendall, A. Resnick and R. E. Rothe for discussion; P.-G. Suh for the gift of the PLC-γ1 antibody; and B. VanRossum for graphics. This research was supported by US Public Health Service Grants and a Research Scientist Award (to S.H.S.), a National Institutes of Health Grant (to D.L.G.), and National Research Service Awards (to R.L.P.).
The authors declare that they have no competing financial interests.
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van Rossum, D., Patterson, R., Sharma, S. et al. Phospholipase Cγ1 controls surface expression of TRPC3 through an intermolecular PH domain. Nature 434, 99–104 (2005). https://doi.org/10.1038/nature03340
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