The lever model of synaptotagmin-1 function

Neurotransmitter release is triggered rapidly by Ca2+ binding to synaptotagmin-1 in cooperation with the soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs). Synaptotagmin-1 is believed to facilitate membrane fusion by inserting the Ca2+-binding loops of its two C2 domains into membranes, thus perturbing the bilayers and/or inducing curvature. However, this direct role has been questioned by the observation that when the synaptotagmin-1 C2B domain binds the SNARE complex, its Ca2+-binding loops point away from the fusion site. Recent data together with older results suggested a natural explanation for this paradox. Molecular dynamics simulations indicate that placing the Ca2+-binding loops close to the fusion site hinders SNARE-mediated membrane fusion. Electron paramagnetic resonance, nuclear magnetic resonance and fluorescence spectroscopy show that, upon Ca2+ binding, the C2B domain reorients on the membrane and can partially dissociate from the membrane-anchored SNARE complex. Electrophysiological studies strongly suggest that such reorientation of the C2B domain with respect to the SNAREs is crucial for neurotransmitter release. In this Hypothesis article, we discuss how these findings have led to a model whereby Ca2+-induced reorientation the C2B domain causes synaptotagmin-1 to act remotely as a lever, pulling the SNARE complex and facilitating SNARE conformational changes that trigger fast membrane fusion.