The regulated exocytotic release of neurotransmitter and hormones is accomplished by a complex protein machinery consisting in its core of SNARE proteins and the calcium sensor synaptotagmin-1. We propose a mechanism where the lipid membrane is intimately involved in coupling calcium sensing to release. We demonstrate that fusion of dense core vesicles, derived from rat PC12 cells is strongly linked to the angle between the cytoplasmic domain of the SNARE complex and the plane of the target membrane. We propose that, as this tilt angle increases, force is exerted on the SNARE transmembrane domains to drive the merger of the two bilayers. The tilt angle dramatically increases upon calcium-mediated binding of synaptotagmin to membranes, strongly depends on the surface electrostatics of the membrane, and is strictly coupled to lipid order of the target membrane.
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