SNARE-mediated Membrane Fusion is a Two-stage Process Driven by Entropic Forces

Overview

Journal FEBS Lett

Specialty Biochemistry

Date 2018 Oct 23

PMID 30346036

Citations 9

Authors

Zachary A McDargh

Anirban Polley

Ben OShaughnessy

Affiliations

Soon will be listed here.

Abstract

SNARE proteins constitute the core of the exocytotic membrane fusion machinery. Fusion occurs when vesicle-associated and target membrane-associated SNAREs zipper into trans-SNARE complexes ('SNAREpins'), but the number required is controversial and the mechanism of cooperative fusion is poorly understood. We developed a highly coarse-grained molecular dynamics simulation to access the long fusion timescales, which revealed a two-stage process. First, zippering energy was dissipated and cooperative entropic forces assembled the SNAREpins into a ring; second, entropic forces expanded the ring, pressing membranes together and catalyzing fusion. We predict that any number of SNAREs fuses membranes, but fusion is faster with more SNAREs.

Citing Articles

Molecular Dynamics Simulation for Membrane Fusion.

Tyoe O, Zhang K, Diao J Methods Mol Biol. 2025; 2887:53-68.

PMID: 39806145 PMC: 11808403. DOI: 10.1007/978-1-0716-4314-3_3.

Three membrane fusion pore families determine the pathway to pore dilation.

Su R, Wang S, McDargh Z, OShaughnessy B Biophys J. 2023; 122(19):3986-3998.

PMID: 37644721 PMC: 10560699. DOI: 10.1016/j.bpj.2023.08.021.

CHARMM-GUI : Past, Current, and Future Developments and Applications.

Feng S, Park S, Choi Y, Im W J Chem Theory Comput. 2023; 19(8):2161-2185.

PMID: 37014931 PMC: 10174225. DOI: 10.1021/acs.jctc.2c01246.

Molecular Dynamics Simulations of the Proteins Regulating Synaptic Vesicle Fusion.

Bykhovskaia M Membranes (Basel). 2023; 13(3).

PMID: 36984694 PMC: 10058449. DOI: 10.3390/membranes13030307.

A hemifused complex is the hub in a network of pathways to membrane fusion.

Warner J, An D, Stratton B, OShaughnessy B Biophys J. 2022; 122(2):374-385.

PMID: 36463406 PMC: 9892611. DOI: 10.1016/j.bpj.2022.12.003.

References

Zhou Q, Lai Y, Bacaj T, Zhao M, Lyubimov A, Uervirojnangkoorn M . Architecture of the synaptotagmin-SNARE machinery for neuronal exocytosis. Nature. 2015; 525(7567):62-7. PMC: 4607316. DOI: 10.1038/nature14975. View

Stratton B, Warner J, Wu Z, Nikolaus J, Wei G, Wagnon E . Cholesterol Increases the Openness of SNARE-Mediated Flickering Fusion Pores. Biophys J. 2016; 110(7):1538-1550. PMC: 4833774. DOI: 10.1016/j.bpj.2016.02.019. View

Stein A, Weber G, Wahl M, Jahn R . Helical extension of the neuronal SNARE complex into the membrane. Nature. 2009; 460(7254):525-8. PMC: 3108252. DOI: 10.1038/nature08156. View

Zhou P, Bacaj T, Yang X, Pang Z, Sudhof T . Lipid-anchored SNAREs lacking transmembrane regions fully support membrane fusion during neurotransmitter release. Neuron. 2013; 80(2):470-83. PMC: 3872166. DOI: 10.1016/j.neuron.2013.09.010. View

Fasshauer D, Margittai M . A transient N-terminal interaction of SNAP-25 and syntaxin nucleates SNARE assembly. J Biol Chem. 2003; 279(9):7613-21. DOI: 10.1074/jbc.M312064200. View

Fortoul N, Singh P, Hui C, Bykhovskaia M, Jagota A . Coarse-Grained Model of SNARE-Mediated Docking. Biophys J. 2015; 108(9):2258-69. PMC: 4423046. DOI: 10.1016/j.bpj.2015.03.053. View

Sorensen J, Fernandez-Chacon R, Sudhof T, Neher E . Examining synaptotagmin 1 function in dense core vesicle exocytosis under direct control of Ca2+. J Gen Physiol. 2003; 122(3):265-76. PMC: 2234490. DOI: 10.1085/jgp.200308855. View

Nikolaus J, Stockl M, Langosch D, Volkmer R, Herrmann A . Direct visualization of large and protein-free hemifusion diaphragms. Biophys J. 2010; 98(7):1192-9. PMC: 2849057. DOI: 10.1016/j.bpj.2009.11.042. View

Sollner T, Whiteheart S, Brunner M, Erdjument-Bromage H, Geromanos S, Tempst P . SNAP receptors implicated in vesicle targeting and fusion. Nature. 1993; 362(6418):318-24. DOI: 10.1038/362318a0. View

10.

Leckband D, Israelachvili J . Intermolecular forces in biology. Q Rev Biophys. 2002; 34(2):105-267. DOI: 10.1017/s0033583501003687. View

11.

Xi Z, Gao Y, Sirinakis G, Guo H, Zhang Y . Single-molecule observation of helix staggering, sliding, and coiled coil misfolding. Proc Natl Acad Sci U S A. 2012; 109(15):5711-6. PMC: 3326506. DOI: 10.1073/pnas.1116784109. View

12.

Risselada H, Kutzner C, Grubmuller H . Caught in the act: visualization of SNARE-mediated fusion events in molecular detail. Chembiochem. 2011; 12(7):1049-55. DOI: 10.1002/cbic.201100020. View

13.

Warner J, OShaughnessy B . Evolution of the hemifused intermediate on the pathway to membrane fusion. Biophys J. 2012; 103(4):689-701. PMC: 3447263. DOI: 10.1016/j.bpj.2012.06.041. View

14.

Francois-Martin C, Rothman J, Pincet F . Low energy cost for optimal speed and control of membrane fusion. Proc Natl Acad Sci U S A. 2017; 114(6):1238-1241. PMC: 5307435. DOI: 10.1073/pnas.1621309114. View

15.

Mostafavi H, Thiyagarajan S, Stratton B, Karatekin E, Warner J, Rothman J . Entropic forces drive self-organization and membrane fusion by SNARE proteins. Proc Natl Acad Sci U S A. 2017; 114(21):5455-5460. PMC: 5448213. DOI: 10.1073/pnas.1611506114. View

16.

Sabatini B, Regehr W . Timing of neurotransmission at fast synapses in the mammalian brain. Nature. 1996; 384(6605):170-2. DOI: 10.1038/384170a0. View

17.

Monticelli L, Kandasamy S, Periole X, Larson R, Tieleman D, Marrink S . The MARTINI Coarse-Grained Force Field: Extension to Proteins. J Chem Theory Comput. 2015; 4(5):819-34. DOI: 10.1021/ct700324x. View

18.

Hernandez J, Kreutzberger A, Kiessling V, Tamm L, Jahn R . Variable cooperativity in SNARE-mediated membrane fusion. Proc Natl Acad Sci U S A. 2014; 111(33):12037-42. PMC: 4143004. DOI: 10.1073/pnas.1407435111. View

19.

Jahn R, Scheller R . SNAREs--engines for membrane fusion. Nat Rev Mol Cell Biol. 2006; 7(9):631-43. DOI: 10.1038/nrm2002. View

20.

Li F, Kummel D, Coleman J, Reinisch K, Rothman J, Pincet F . A half-zippered SNARE complex represents a functional intermediate in membrane fusion. J Am Chem Soc. 2014; 136(9):3456-64. PMC: 3985920. DOI: 10.1021/ja410690m. View