The syt dock has two calcium-binding domains in its cytoplasmic region, called C2A and C2B. “What we discovered is that there are two modes of binding to PIP2 mediated by the C2B domain of syt,” says Chapman. In the absence of calcium, syt binds PIP2 weakly, lying on its side so that C2B contacts the PIP2 head group. Once the C2A and C2B domains bind to calcium, however, the protein flips over to allow the opposite face of C2B to bind to PIP2.
In this conformation, syt inserts membrane penetration prongs into the plasma membrane, potentially facilitating fusion with the secretory vesicle membrane and accelerating exocytosis. Thus, when calcium enters the cell, syt is already poised so that the first membrane C2B encounters is the plasma membrane. In other words, the syt-PIP2 interaction essentially steers the synaptic vesicle to the plasma membrane in preparation for exocytosis. ▪