Phospholipase Cγ1 controls surface expression of TRPC3 through an intermolecular PH domain

Abstract

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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Figure 1: The PLC-γ1 PH-c domain binds directly to amino acids 40–46 in TRPC3.
Figure 2: TRPC3 possesses an invisible PH-n domain at the site of PLC-γ1 PH-c binding.
Figure 3: Interaction between PLC-γ1 PH-c and TRPC3 confers lipid binding and affects membrane expression.
Figure 4: Intermolecular PH-like domain formation controls the surface expression of TRPC3.

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Acknowledgements

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.).

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Correspondence to Solomon H. Snyder.

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The authors declare that they have no competing financial interests.

Supplementary information

Supplementary Figures 1-3

Complementation analyses identify PH domain code within TRPC3, smallwing, alpha 1 syntrophin, syngap and TRPV1. (PDF 447 kb)

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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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