Synaptotagmin-Mediated Bending of the Target Membrane Is a Critical Step in Ca2+-Regulated Fusion
Open accessAbstract
Decades ago it was proposed that exocytosis involves invagination of the target membrane, resulting in a highly localized site of contact between the bilayers destined to fuse. The vesicle protein synaptotagmin-I (syt) bends membranes in response to Ca(2+), but whether this drives localized invagination of the target membrane to accelerate fusion has not been determined. Previous studies relied on reconstituted vesicles that were already highly curved and used mutations in syt that were not selective for membrane-bending activity. Here, we directly address this question by utilizing vesicles with different degrees of curvature. A tubulation-defective syt mutant was able to promote fusion between highly curved SNARE-bearing liposomes but exhibited a marked loss of activity when the membranes were relatively flat. Moreover, bending of flat membranes by adding an N-BAR domain rescued the function of the tubulation-deficient syt mutant. Hence, syt-mediated membrane bending is a critical step in membrane fusion.
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Upon Ca2+ binding to the Syt1 C2B domain, the Ca2+ binding loops partially insert into the membrane with a preference for membrane curvature, possibly supported by ionic interactions via the polybasic region and with continuing maintenance of the Syt1-SNARE interface.
“Upon Ca2+ binding to the Syt1 C2B domain, the Ca2+ binding loops partially insert into the membrane23 with a preference for membrane curvature20,21, possibly supported by ionic interactions via the polybasic region and with continuing maintenance of the Syt1-SNARE interface.”
From Architecture of the synaptotagmin–SNARE machinery for neuronal exocytosis (2015) · cites this paper as [20]
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Research works printed but not linked: 37
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“…of Syt1 that have been proposed to facilitate membrane fusion such as bilayer perturbation ( 35 , 37 , 38 ), induction of membrane curvature ( 39 , 40 ), or membrane bridging ( 42 , 43 ) can cooperate with the SNAREs to induce fast membrane fusion, particularly after molecular dynamics (MD)…”
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“As mentioned earlier, this is triggered by the binding of free calcium ions to Syt1, which drives altered interactions with both the assembled SNARE complex and plasma membrane, resulting in the synchronisation of neurotransmitter release to neuronal activity (Hui et al. 2009; Toulmé et al. 2024).”
- Authors
- Hui, E., Johnson, C. P., Yao, J., Dunning, F. M., & Chapman, E. R.
- Affiliations
- Howard Hughes Medical Institute (US)
- Corresponding author
- Chapman, Edwin R.
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2009-08
- Volume
- 138
- Issue
- 4
- Pages
- 709-721
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC2758036
- OpenAlex
- W2121966104
- Cited by
- 291
- References
- 0
- Citations by year
- 2026: 4 · 2025: 7 · 2024: 9 · 2023: 11 · 2022: 17 · 2021: 12 · 2020: 12 · 2019: 15 · 2018: 17 · 2017: 19 · 2016: 16 · 2015: 24 · 2014: 23 · 2013: 23 · 2012: 30
- FWCI
- 12.17
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institute of Mental Health (MH61876, R01MH061876)
- 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 › Extracellular vesicles in disease
- Keywords
- synaptotagmin-1, membrane bending, exocytosis, membrane fusion, calcium regulation, N-BAR domain, membrane curvature
- MeSH terms
- Animals, Brain Chemistry, Calcium, Cell Membrane, Exocytosis, Liposomes, Mutation, Intracellular Signaling Peptides and Proteins, SNARE Proteins, Synaptotagmins
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