SNARE Machinery Is Optimized for Ultrafast Fusion

Proceedings of the National Academy of Sicences, 116(7): 2435-2442 🔗 📘

Abstract

SNARE proteins zipper to form complexes (SNAREpins) that power vesicle fusion with target membranes in a variety of biological processes. A single SNAREpin takes about 1 s to fuse two bilayers, yet a handful can ensure release of neurotransmitters from synaptic vesicles much faster: in a 10th of a millisecond. We propose that, similar to the case of muscle myosins, the ultrafast fusion results from cooperative action of many SNAREpins. The coupling originates from mechanical interactions induced by confining scaffolds. Each SNAREpin is known to have enough energy to overcome the fusion barrier of 25–35 kBT; however, the fusion barrier only becomes relevant when the SNAREpins are nearly completely zippered, and from this state, each SNAREpin can deliver only a small fraction of this energy as mechanical work. Therefore, they have to act cooperatively, and we show that at least three of them are needed to ensure fusion in less than a millisecond. However, to reach the pre-fusion state collectively, starting from the experimentally observed half-zippered metastable state, the SNAREpins have to mechanically synchronize, which takes more time as the number of SNAREpins increases. Incorporating this somewhat counterintuitive idea in a simple coarse-grained model results in the prediction that there should be an optimum number of SNAREpins for sub-millisecond fusion: three to six over a wide range of parameters. Interestingly, in situ cryoelectron microscope tomography has very recently shown that exactly six SNAREpins participate in the fusion of each synaptic vesicle. This number is in the range predicted by our theory.

Significance

We propose a mechanistic description of fusion of a synaptic vesicle with a target membrane executed by a team of zippering SNARE complexes (SNAREpins). In the context of neurotransmitters release, this process naturally decomposes in two steps with rates that depend on the number of SNAREpins. The first step is synchronized escape from the metastable half-zippered state, which gets exponentially more sluggish as increases. The second step is fusion of two closely tethered membranes, which is accelerated exponentially by an increase of. The trade-off between these two antagonist trends results in a sharply optimal number of SNAREpins, which ensures fusion at the physiological sub-millisecond timescale. The optimization mechanism revealed by this contribution is generic and likely applies to the wide class of biological processes involving SNARE mediated membrane fusion.

Reference

@article{manca-2019,
  title = {SNARE Machinery Is Optimized for Ultrafast Fusion},
  author = {Manca, Fabio and Pincet, Frederic and Truskinovsky, Lev and Rothman, James E. and Foret, Lionel and Caruel, Matthieu},
  year = {2019},
  month = feb,
  journal = {Proceedings of the National Academy of Sciences},
  volume = {116},
  number = {7},
  pages = {2435--2442},
  doi = {10/gmn5g3},
  langid = {en},
}