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Mechanisms of SNARE proteins in membrane fusion

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Jahn, Reinhard, Cafiso, David C., Tamm, Lukas K.·2024·Nature Reviews Molecular Cell Biology
DOI 10.1038/s41580-023-00668-xPMC PMC11578640
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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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  • Electropores promote metastable interbilayer splays, lowering the energy barrier for peripore stalk formation even at membrane separations >1 nm, conditions under which strong hydration repulsion would otherwise hinder stalk formation.

    “Our proposed membrane fusion pathway centers on electropores, which promote metastable interbilayer splays, lowering the energy barrier for peripore stalk formation even at membrane separations >1 nm -conditions under which strong hydration repulsion would otherwise hinder stalk formation 4,7,37 .”

    From Fusion of lipid membranes: an alternative pathway (2026) · cites this paper as [7]

    In “Step III: lipid tail splaying and fusion stalk formation” (page unavailable), the paper says lipid-tail splaying precedes stalk formation and that perturbing the membrane interface can lower the energy barrier. “Step II: tight docking” also discusses repulsive forces. The cited passages do not establish that electropores promote metastable interbilayer splays or peripore stalks at separations greater than 1 nm. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Complete fusion proceeds by formation and expansion of a fusion pore within the hemifusion diaphragm, yielding a fully fused membrane.

    “Complete fusion then proceeds by formation and expansion of a fusion pore within this diaphragm, yielding a fully fused membrane 5,7 , as illustrated in Fig. 1A.”

    From Fusion of lipid membranes: an alternative pathway (2026) · cites this paper as [7]

    The sections on fusion pore opening and expansion describe these as the final steps of fusion. But Step IV says a pore can begin at the centre of a stalk or the rim of a hemifusion diaphragm, not necessarily within a diaphragm; Step III adds that extended diaphragms may be dead ends. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Lipid headgroups forming membrane surfaces are highly hydrophilic and hydrated, imposing a high energy barrier for two membranes to fuse due to hydration repulsion.

    “The lipidic headgroups forming the membranes' surface are highly hydrophilic and hydrated, imposing a high energy barrier for two membranes to fuse due to hydration repulsion [4][5][6][7] .”

    From Fusion of lipid membranes: an alternative pathway (2026) · cites this paper as [7]

  • Fusogenic proteins mediate membrane fusion by pulling the membranes into contact to overcome the high energy barrier imposed by hydration repulsion.

    “It is often considered in the presence of fusogenic proteins, which mediate the fusion by pulling the membranes into contact to overcome the high energy barrier imposed by hydration repulsion [4][5][6][7] .”

    From Fusion of lipid membranes: an alternative pathway (2026) · cites this paper as [7]

  • Fusogenic proteins, most notably SNAREs, are key drivers of membrane fusion because by pulling membranes together to under 1 nm they reduce lipid hydration and lower the hydration-repulsion energy barrier.

    “Fusogenic proteins-most notably SNAREs-are widely recognized as key drivers of membrane fusion because by pulling the membranes together to under 1 nm they reduce lipid hydration and thus lower the hydration-repulsion energy barrier 7,13 .”

    From Fusion of lipid membranes: an alternative pathway (2026) · cites this paper as [7]

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Authors
Jahn, R., Cafiso, D. C., & Tamm, L. K.
Affiliations
  • Max Planck Institute for Multidisciplinary Sciences (DE)
  • University of Virginia (US)
Corresponding author
Jahn, Reinhard
ORCID
Venue
Nature Reviews Molecular Cell Biology
Publisher
Springer Science and Business Media LLC
Published
2023-10-17
Volume
25
Issue
2
Pages
101-118
ISSN
  • 1471-0072 (ISSN-L)
  • 1471-0080
DOI
10.1038/s41580-023-00668-x
PMC
PMC11578640
OpenAlex
W4387702852
Cited by
248
References
8
Citations by year
2026: 92 · 2025: 113 · 2024: 40 · 2023: 3
FWCI
7.79
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Reviews Molecular Cell Biology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • GoeScholar The Publication Server of the Georg-August-Universität Göttingen (Georg-August-Universität Göttingen) (submittedVersion, cc-by)
Funders
  • Georg-August-Universität Göttingen
  • National Institutes of Health (GM072694)
  • National Institute of General Medical Sciences (P01GM072694)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Lipid Membrane Structure and Behavior
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
Keywords
SNARE proteins, membrane fusion, SNARE complex assembly, fusion pore, accessory proteins, energy barrier, organelle fusion, fusion pore expansion
MeSH terms
Cell Membrane, Membrane Fusion, SNARE Proteins

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