Synaptotagmin-1 may be a distance regulator acting upstream of SNARE nucleation

Synaptotagmin-1 triggers Ca(2+)-sensitive, rapid neurotransmitter release by promoting the interaction of SNARE proteins between the synaptic vesicles and the plasma membrane. How synaptotagmin-1 promotes this interaction is controversial, and the massive increase in membrane fusion efficiency of Ca(2+)-synaptotagmin-1 has not been reproduced in vitro. However, previous experiments have been performed at relatively high salt concentrations, screening potentially important electrostatic interactions. Using functional reconstitution in liposomes, we show here that at low ionic strength SNARE-mediated membrane fusion becomes strictly dependent on both Ca(2+) and synaptotagmin-1. Under these conditions, synaptotagmin-1 functions as a distance regulator: tethering the liposomes too far for SNARE nucleation in the absence of Ca(2+), but brings the liposomes close enough for membrane fusion in the presence of Ca(2+). These results may explain how the relatively weak electrostatic interactions of synaptotagmin-1 with membranes substantially accelerate fusion.