How Synaptotagmin Promotes Membrane Fusion

TLDR

Synaptic vesicle exocytosis is a SNARE‑dependent process triggered by presynaptic depolarization‑induced Ca²⁺ influx, with synaptotagmin‑1 acting as the Ca²⁺ sensor and the bilayer‑bilayer fusion activation energy being very high (~40 k_BT). We show that Ca²⁺ binding to synaptotagmin‑1 lowers the fusion activation barrier by inserting its C2 domains into target membranes to create high positive curvature, thereby triggering Ca²⁺‑dependent plasma‑membrane buckling and SNARE zippering and suggesting a broadly used fusion mechanism.

Abstract

Synaptic vesicles loaded with neurotransmitters are exocytosed in a soluble N -ethylmaleimide–sensitive factor attachment protein receptor (SNARE)–dependent manner after presynaptic depolarization induces calcium ion (Ca 2+ ) influx. The Ca 2+ sensor required for fast fusion is synaptotagmin-1. The activation energy of bilayer-bilayer fusion is very high (≈40 k B T ). We found that, in response to Ca 2+ binding, synaptotagmin-1 could promote SNARE-mediated fusion by lowering this activation barrier by inducing high positive curvature in target membranes on C2-domain membrane insertion. Thus, synaptotagmin-1 triggers the fusion of docked vesicles by local Ca 2+ -dependent buckling of the plasma membrane together with the zippering of SNAREs. This mechanism may be widely used in membrane fusion.