The group's initial example of a split domain comes in the context of a Ca2+ entry system. In this system, neurotransmitters bind receptors that trigger production of inositol 1,4,5-trisphosphate (IP3), which in turn prompts release of intracellular Ca2+ stores and entry of extracellular Ca2+ through TRPC3 channels. Snyder and colleagues previously established that phospholipase Cγ1 (PLC-γ1) was needed for this latter TRPC3 action, independent of PLC-γ1's enzymatic activity in generating IP3.
They now report that the binding of TRPC3 and PLC-γ1 to each other brings together two halves of a split PH domain, a motif associated with the binding of lipids and other proteins. Mutation of the partial PH domains changes the lipid-binding profile of the TRPC3–PLC-γ1 complex, and reduces the amount of TRPC3 at the plasma membrane 24 h after stimulation.
The phenomenon of split domains may be widespread. A modified search algorithm spotted not only the half-domains in TRPC3 and PLC-γ1 but also split domains in additional proteins. “It has opened up a whole new world,” says Snyder. “It will amplify perhaps many-fold the number of protein recognition motifs.” This profusion of motifs, he says, allows the cell to deliver on a promise: “Everything is hand delivered.”