Zhang, X;
Rebane, AA;
Ma, L;
Li, F;
Jiao, J;
Qu, H;
Pincet, F;
... Zhang, Y; + view all
(2016)
Stability, folding dynamics, and long-range conformational transition of the synaptic t-SNARE complex.
Proceedings of the National Academy of Sciences of the United States of America
, 113
(50)
E8031-E8040.
10.1073/pnas.1605748113.
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Abstract
Synaptic soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs) couple their stepwise folding to fusion of synaptic vesicles with plasma membranes. In this process, three SNAREs assemble into a stable four-helix bundle. Arguably, the first and rate-limiting step of SNARE assembly is the formation of an activated binary t-SNARE complex on the plasma membrane, which then zippers with the v-SNARE on the vesicle to drive membrane fusion. However, the t-SNARE complex readily misfolds and its structure, stability, and dynamics are elusive. Using single-molecule force spectroscopy, we modeled synaptic t-SNARE complex as a parallel three-helix bundle with a small frayed Cterminus. The helical bundle sequentially folded in an N-terminal domain (NTD) and a C-terminal domain (CTD) separated by a central ionic layer, with total unfolding energy of ∼17 kBT. Peptide binding to the CTD activated the t-SNARE complex to initiate NTD zippering with the v-SNARE, a mechanism likely shared by Munc18-1. The NTD zippering then dramatically stabilized the CTD, facilitating further SNARE zippering. The subtle bidirectional tSNARE conformational switch was mediated by the ionic layer. Thus, the t-SNARE complex acts as a switch to enable fast and controlled SNARE zippering required for synaptic vesicle fusion and neurotransmission.
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