Abstract
Soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs) are a family of small conserved eukaryotic proteins that mediate membrane fusion between organelles and with the plasma membrane. SNAREs are directly or indirectly anchored to membranes. Prior to fusion, complementary SNAREs assemble between membranes with the aid of accessory proteins that provide a scaffold to initiate SNARE zippering, pulling the membranes together and mediating fusion. Recent advances have enabled the construction of detailed models describing bilayer transitions and energy barriers along the fusion pathway and have elucidated the structures of SNAREs complexed in various states with regulatory proteins. In this Review, we discuss how these advances are yielding an increasingly detailed picture of the SNARE-mediated fusion pathway, leading from first contact between the membranes via metastable non-bilayer intermediates towards the opening and expansion of a fusion pore. We describe how SNARE proteins assemble into complexes, how this assembly is regulated by accessory proteins and how SNARE complexes overcome the free energy barriers that prevent spontaneous membrane fusion.
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Acknowledgements
The authors thank H. Grubmüller, M. Müller, S. Pribićević and A. Stein (all Max-Planck Institute for Multidisciplinary Sciences, Göttingen) for critical comments, and A. Chizhik (Third Institute of Physics, University of Göttingen) for help in preparing Fig. 1. Work in the authors’ laboratory was supported by Program Project Grant 2 P01 GM072694 from the National Institutes of Health (NIH) awarded to L.K.T., R.J. and D.S.C.
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R.J. researched data for the article. All authors contributed substantially to discussion of the content. R.J. and L.K.T. wrote the article. All authors reviewed and/or edited the manuscript before submission.
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Glossary
- Black lipid membranes
-
An experimental model in which single bilayers span a hole 10–100 µm wide created in a Teflon sheet immersed in aqueous media. They appear black because light reflected off the back of the membrane interferes with light reflected from the front.
- Content mixing
-
Mixing of the aqueous interior of two vesicles undergoing fusion. Only occurs after opening of a fusion pore.
- Content release
-
Release of the enclosed content of a vesicle into the environment upon fusion of a vesicle with a planar membrane.
- Hysteresis
-
The state of a system depends on the history (or pathway) by which the state has been reached. Hysteretic systems therefore cannot be modelled using equilibrium thermodynamics where a system can only assume a single state under a defined set of conditions, independent of how it got there.
- kT
-
The product of the Boltzmann constant k with the absolute temperature T, a measure of the thermal energy per molecule. Can be converted into other energy units such as calories, joules or electronvolts.
- Lipid mixing
-
Mixing of membrane lipids during fusion, often describing the stage when the contacting lipid leaflets have mixed and the two distal leaflets remain separated.
- Secretory pathway
-
A system that connects most intracellular membranes, including the plasma membrane of eukaryotic cells, by vesicles that dissociate from the ‘donor’ membrane and then fuse with the target membrane, including the plasma membrane, resulting in secretion of the vesicle content.
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Jahn, R., Cafiso, D.C. & Tamm, L.K. Mechanisms of SNARE proteins in membrane fusion. Nat Rev Mol Cell Biol 25, 101–118 (2024). https://doi.org/10.1038/s41580-023-00668-x
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