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Sci. STKE, 8 March 2005
Vol. 2005, Issue 274, p. tw84
[DOI: 10.1126/stke.2742005tw84]


PROTEIN DOMAINS It Takes Two to Make a PH Domain

Pleckstrin homology (PH) domains confer specific lipid-binding properties to the proteins in which they are found. Not all PH domains are readily identifiable through available sequence-analysis methods: Some are discontinuous with the N- and C-terminal portions of the PH domain separated within the molecule, and some are formed by nonconsensus sequences that can adopt a PH-like structure. Van Rossum et al. report that TRPC3 (a member of the transient receptor potential protein family of cation channels) and phospholipase C-{gamma}1 (PLC-{gamma}1) interact to form an intermolecular PH-like domain that controls plasma membrane expression of the TRPC3 channel through binding to specific lipids. TRPC3 interacts with a C-terminal portion of a partial PH domain in PLC-{gamma}1, called PH-c. The authors developed an algorithm that slides a partial consensus sequence across a target protein and then uses PH domain complementation to detect PH-like domains. This method identified the residues of TRPC3 that are known to bind PLC-{gamma}1, as well as unconventional PH domains in several other proteins known to form a PH-like structure. In vitro translated PLC-{gamma}1 PH-c peptide and wild-type or mutant TRPC3 that could not bind PLC-{gamma}1 PH-c were analyzed for lipid binding. Only in the presence of both wild-type TRPC3 and PLC-{gamma}1 PH-c was binding to phosphatidylinositol 4,5 bisphosphate (PI4,5P2) detected. The activity and surface expression of TRPC3 in transfected cells required both PLC-{gamma}1 binding and lipid binding, because mutations that disrupted either decreased channel activity and abundance at the cell surface. This provides evidence that an intermolecular lipid-binding PH domain controls surface expression of TRPC3. The formation of intermolecular PH domains provides a model for lipid regulation of other proteins that lack conventional PH domains, and the algorithm provides a mechanism to detect these "invisible" PH domains.

D. B. van Rossum, R. L. Patterson, S. Sharma, R. K. Barrow, M. Kornberg, D. L. Gill, S. H. Snyder, Phospholipase C{gamma}1 controls surface expression of TRPC3 through an intermolecular PH domain. Nature 434, 99-104 (2005). [PubMed]

Citation: It Takes Two to Make a PH Domain. Sci. STKE 2005, tw84 (2005).

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