PerspectiveCell Biology

Staging Membrane Fusion

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Science  14 Sep 2012:
Vol. 337, Issue 6100, pp. 1300-1301
DOI: 10.1126/science.1228654

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Upon arrival of a nerve impulse, neurons release neurotransmitters contained within synaptic vesicles to transmit signals to other neurons, thus enabling a myriad of neural functions. Neurotransmitter release is mediated by the soluble N-ethylmaleimide–sensitive factor attachment protein receptor (SNARE) proteins synaptobrevin, syntaxin-1, and SNAP-25, which govern the fusion of synaptic vesicles with the plasma membrane. Assembly of the tight complex formed by the SNAREs is believed to provide the energy for fusion (1, 2) and to occur in steps, zippering from the amino terminus to the carboxyl terminus (3) (see the figure). Biophysical data in solution (4, 5) and studies of SNARE complexes anchored at separate surfaces using surface force apparatus (6) or atomic force microscopy (7) supported this notion and provided insights into the zippering forces. However, fundamental questions remained about the energy landscape and the overall free energy of SNARE complex assembly. On page 1340 of this issue, Gao et al. (8) combine a clever design with a high-tech optical approach to dissect neuronal SNARE complex assembly into three steps and to determine the associated free energies. This remarkable technical achievement has profound implications to understand the mechanism of neurotransmitter release.