Parsing p53 activity

Tucker, and Edwin Chapman (University of Wisconsin, Madison, WI) find that PIP 2 is a plasma membrane dock for synaptotagmin-1 (syt), a transmembrane protein localized in secretory vesicle membranes, when calcium is absent. This dock may ensure speedy and directed fusion in response to calcium influx. The syt dock has two calcium-binding domains in its cytoplasmic region, called C 2 A and C 2 B. “What we discovered is that there are two modes of binding to PIP 2 mediated by the C 2 B domain of syt,” says Chapman. In the absence of calcium, syt binds PIP 2 weakly, lying on its side so that C 2 B contacts the PIP 2 head group. Once the C 2 A and C 2 B domains bind to calcium, however, the protein flips over to allow the opposite face of C 2 B to bind to PIP 2 . 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 C 2 B encounters is the plasma membrane. In other words, the syt-PIP 2 interaction essentially steers the synaptic vesicle to the plasma membrane in preparation for exocytosis.