Close membrane-membrane proximity induced by Ca2+-dependent multivalent binding of synaptotagmin-1 to phospholipids
Abstract
Synaptotagmin acts as a Ca(2+) sensor in neurotransmitter release through its two C(2) domains. Ca(2+)-dependent phospholipid binding is key for synaptotagmin function, but it is unclear how this activity cooperates with the SNARE complex involved in release or why Ca(2+) binding to the C(2)B domain is more crucial for release than Ca(2+) binding to the C(2)A domain. Here we show that Ca(2+) induces high-affinity simultaneous binding of synaptotagmin to two membranes, bringing them into close proximity. The synaptotagmin C(2)B domain is sufficient for this ability, which arises from the abundance of basic residues around its surface. We propose a model wherein synaptotagmin cooperates with the SNAREs in bringing the synaptic vesicle and plasma membranes together and accelerates membrane fusion through the highly positive electrostatic potential of its C(2)B domain.
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In retrospect, the increased ensemble lipid mixing result was probably caused by an effect on vesicle association since multivalent binding of the soluble Syt1 C2AB fragment can induce vesicle clustering.
“However, in retrospect, this result was probably caused by an effect on vesicle association since multivalent binding of the soluble Syt1 C2AB fragment can induce vesicle clustering19.”
From Architecture of the synaptotagmin–SNARE machinery for neuronal exocytosis (2015) · cites this paper as [19]
Cites
Crystal structure of a SNARE complex involved in synaptic exocytosis at 2.4 Å resolution
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A single C2 domain from synaptotagmin I is sufficient for high affinity Ca2+/phospholipid binding.
Davletov, B. A., & Südhof, T. C. (1993) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(19)74326-9 · Cited by 480 · see citing works
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The Morphological and Molecular Nature of Synaptic Vesicle Priming at Presynaptic Active Zones
Imig, C., Min, S.-W., Krinner, S., Arancillo, M., Rosenmund, C., Südhof, T. C., Rhee, J., Brose, N., & Cooper, B. H. (2014) · Neuron · doi:10.1016/j.neuron.2014.10.009 · Cited by 389 · see citing works
Self-citationArchitecture of the synaptotagmin–SNARE machinery for neuronal exocytosis
Zhou, Q., Lai, Y., Bacaj, T., Zhao, M., Lyubimov, A. Y., Uervirojnangkoorn, M., Zeldin, O. B., Brewster, A. S., Sauter, N. K., Cohen, A. E., et al. (2015) · Nature · doi:10.1038/nature14975 · Cited by 348 · see citing works
Self-citationA genomic view of the sea urchin nervous system
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Mechanism of neurotransmitter release coming into focus
Rizo, J. (2018) · Protein Science · doi:10.1002/pro.3445 · Cited by 210 · see citing works
Self-citationLai, Y., Lou, X., Jho, Y., Yoon, T.-Y., & Shin, Y.-K. (2013) · Biochemical Journal · doi:10.1042/bj20130949 · Cited by 28 · see citing works
Toulmé, E., Salazar Lázaro, A., Trimbuch, T., Rizo, J., & Rosenmund, C. (2024) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2409636121 · Cited by 27 · see citing works
“…Ca 2+ influx triggers chelation of Ca 2+ between the top loops of the C 2 B domain and the phospholipid membrane, and the insertion of both Ca 2+ - binding loops into the membrane ( 32 , 39 , 40 ), leading to an approximately perpendicular orientation with respect to the bilayer ( 41 ).”
Self-citationA lever hypothesis for Synaptotagmin-1 action in neurotransmitter release
Jaczynska, K., Esser, V., Xu, J., Sari, L., Lin, M. M., Rosenmund, C., & Rizo, J. (2025) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2417941121 · Cited by 13 · see citing works
“…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) simulations revealed a natural…”
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- Authors
- Araç, D., Chen, X., Khant, H. A., Ubach, J., Ludtke, S. J., Kikkawa, M., Johnson, A. E., Chiu, W., Südhof, T. C., & Rizo, J.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- Baylor College of Medicine (US)
- Texas A&M Health Science Center (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Rizo, Josep
- ORCID
- Venue
- Nature Structural & Molecular Biology
- Published
- 2006-02-19
- Volume
- 13
- Issue
- 3
- Pages
- 209-217
- ISSN
- 1545-9985 (ISSN-L)
- 1545-9993
- OpenAlex
- W2021285837
- Cited by
- 256
- References
- 2
- Citations by year
- 2026: 1 · 2025: 5 · 2024: 6 · 2023: 5 · 2022: 9 · 2021: 10 · 2020: 8 · 2019: 4 · 2018: 11 · 2017: 8 · 2016: 12 · 2015: 15 · 2014: 18 · 2013: 20 · 2012: 17
- FWCI
- 8.95
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Structural & Molecular Biology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Foundation for the National Institutes of Health
- Welch Foundation
- National Institute of General Medical Sciences (R01GM026494, GM26494)
- National Institute of Neurological Disorders and Stroke (NS40944, R01NS040944)
- National Center for Research Resources (P41RR002250)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Lipid Membrane Structure and Behavior
- Keywords
- synaptotagmin-1, C2B domain, C2A domain, calcium binding, phospholipid binding, multivalent binding, SNARE complex, synaptic vesicle fusion, neurotransmitter release, electrostatic potential, membrane fusion
- MeSH terms
- Animals, Binding Sites, Calcium, Liposomes, Membrane Fusion, Models, Biological, Models, Molecular, Phospholipids, Protein Binding, Spectrometry, Fluorescence, Synaptic Vesicles, Protein Structure, Secondary, Protein Structure, Tertiary, Pliability, Synaptotagmins, Rats
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