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.
Subscribe to Journal
Get full journal access for 1 year
only $3.90 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Runnels, L. W., Yue, L. & Clapham, D. E. The TRPM7 channel is inactivated by PIP(2) hydrolysis. Nature Cell Biol. 4, 329–336 (2002)
Prescott, E. D. & Julius, D. A modular PIP2 binding site as a determinant of capsaicin receptor sensitivity. Science 300, 1284–1288 (2003)
Suh, B. C. & Hille, B. Recovery from muscarinic modulation of M current channels requires phosphatidylinositol 4,5-bisphosphate synthesis. Neuron 35, 507–520 (2002)
Patterson, R. L. et al. Phospholipase C-γ is required for agonist-induced Ca2+ entry. Cell 111, 529–541 (2002)
DiNitto, J. P., Cronin, T. C. & Lambright, D.G. Membrane recognition and targeting by lipid-binding domains. Sci. STKE. re16 (2003).
Rebecchi, M. J. & Scarlata, S. Pleckstrin homology domains: a common fold with diverse functions. Annu. Rev. Biophys. Biomol. Struct. 27, 503–528 (1998)
Marchler-Bauer, A. et al. CDD: a curated Entrez database of conserved domain alignments. Nucleic Acids Res. 31, 383–387 (2003)
Bateman, A. et al. The Pfam protein families database. Nucleic Acids Res. 32, D138–D141 (2004)
Gattiker, A., Gasteiger, E. & Bairoch, A. ScanProsite: a reference implementation of a PROSITE scanning tool. Appl. Bioinform. 1, 107–108 (2002)
Letunic, I. et al. SMART 4.0: towards genomic data integration. Nucleic Acids Res. 32, D142–D144 (2004)
Jogl, G. et al. Crystal structure of the BEACH domain reveals an unusual fold and extensive association with a novel PH domain. EMBO J. 21, 4785–4795 (2002)
Gervais, V. et al. TFIIH contains a PH domain involved in DNA nucleotide excision repair. Nature Struct. Mol. Biol. 11, 616–622 (2004)
Vetter, I. R., Nowak, C., Nishimoto, T., Kuhlmann, J. & Wittinghofer, A. Structure of a Ran-binding domain complexed with Ran bound to a GTP analogue: implications for nuclear transport. Nature 398, 39–46 (1999)
Ma, H. T. et al. Requirement of the inositol trisphosphate receptor for activation of store-operated Ca2+ channels. Science 287, 1647–1651 (2000)
Baranano, D. E. et al. A mammalian iron ATPase induced by iron. J. Biol. Chem. 275, 15166–15173 (2000)
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.
About this article
Cite this article
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
Molecular Psychiatry (2017)
Nature Communications (2017)
Molecular Neurobiology (2016)
Cellular and Molecular Life Sciences (2013)
Regulation of the transient receptor potential channel TRPA1 by its N-terminal ankyrin repeat domain
Journal of Molecular Modeling (2013)