Investigation of SNARE-Mediated Membrane Fusion Mechanism Using Atomic Force Microscopy

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Abstract
Membrane fusion is driven by specialized proteins that reduce the free energy penalty for the fusion process. In neurons and secretory cells, soluble N-ethylmaleimide-sensitive factor-attachment protein (SNAP) receptors (SNAREs) mediate vesicle fusion with the plasma membrane during vesicular content release. Although, SNAREs have been widely accepted as the minimal machinery for membrane fusion, the specific mechanism for SNARE-mediated membrane fusion remains an active area of research. Here, we summarize recent findings based on force measurements acquired in a novel experimental system that uses atomic force microscope (AFM) force spectroscopy to investigate the mechanism(s) of membrane fusion and the role of SNAREs in facilitating membrane hemifusion during SNARE-mediated fusion. In this system, protein-free and SNARE-reconstituted lipid bilayers are formed on opposite (trans) substrates and the forces required to induce membrane hemifusion and fusion or to unbind single v-/t-SNARE complexes are measured. The obtained results provide evidence for a mechanism by which the pulling force generated by interacting trans-SNAREs provides critical proximity between the membranes and destabilizes the bilayers at fusion sites by broadening the hemifusion energy barrier and consequently making the membranes more prone to fusion.

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