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A single C2 domain from synaptotagmin I is sufficient for high affinity Ca2+/phospholipid binding.
Open accessAbstract
Synaptotagmin I is a Ca(2+)- and phospholipid-binding protein of synaptic vesicles with an essential function in neurotransmission. Ca2+/phospholipid binding by synaptotagmin I may be mediated by its C2 domains, sequence motifs that have been implicated in the Ca2+ regulation of a variety of proteins. However, it is currently unknown if C2 domains are sufficient for Ca2+/phospholipid binding or if they even directly participate in Ca2+/phospholipid binding. In order to address this question, we have studied the Ca2+/phospholipid-binding properties of the first C2 domain of synaptotagmin I. Our results show that this C2 domain by itself binds Ca2+ and phospholipids with high affinity (half-maximal binding at 4-6 microM free Ca2+) and exhibits strong positive cooperativity. The C2 domain is specific for negatively charged phospholipids and for those divalent cations that are known to stimulate synaptic vesicle exocytosis (Ca2+ > Sr2+, Ba2+ >>> Mg2+). These studies establish that C2 domains can serve as independently folding Ca2+/phospholipid-binding domains. Furthermore, the cation specificity and the cooperativity of Ca2+ binding by the C2 domain from synaptotagmin I support a role for this protein in mediating the Ca2+ signal in neurotransmitter release.
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“Syt1 binds in a Ca2+-dependent manner to anionic membranes; during binding, anionic phospholipids and synaptotagmin C2 domains together coordinate calcium14–17.”
From Architecture of the synaptotagmin–SNARE machinery for neuronal exocytosis (2015) · cites this paper as [14]
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Linial, M., & Parnas, D. (1996) · Biochimica et Biophysica Acta (BBA) - Reviews on Biomembranes · doi:10.1016/0304-4157(96)00007-x · Cited by 30
Avenues to molecular imaging of dying cells: Focus on cancer
Rybczynska, A. A., Boersma, H. H., de Jong, S., Gietema, J. A., Noordzij, W., Dierckx, R., Elsinga, P. H., & van Waarde, A. (2018) · Medicinal Research Reviews · doi:10.1002/med.21495 · Cited by 40
Structure-Based Designed Nano-Dysferlin Significantly Improves Dysferlinopathy in BLA/J Mice
Llanga, T., Nagy, N., Conatser, L., Dial, C. F., Sutton, R. B., & Hirsch, M. L. (2017) · Molecular Therapy · doi:10.1016/j.ymthe.2017.05.013 · Cited by 54
“In general, C2 domains are modular protein domains that can bind to the inner leaflet of phospholipid membranes.(23) Most C2 domains bind to membranes in a Ca-dependent manner, but there are some that do not.”
BackgroundAncestral genetic complexity of arachidonic acid metabolism in Metazoa.
Yuan, D., Zou, Q., Yu, T., Song, C.-K., Huang, S.-F., Chen, S.-W., Ren, Z., & Xu, A. (2014) · Biochimica et Biophysica Acta · doi:10.1016/j.bbalip.2014.04.009 · Cited by 32
“C2 domain is believed to be involved in calcium-dependent phospholipids binding [43] and in membrane targeting processes, such as subcellular localization.”
BackgroundC2 domain is responsible for targeting rice phosphoinositide specific phospholipase C
Rupwate, S. D., & Rajasekharan, R. (2011) · Plant Molecular Biology · doi:10.1007/s11103-011-9862-1 · Cited by 32
Wang, F., Fang, W.-S., Zhang, M.-R., Zhao, M., Liu, B., Wang, Z.-Z., Hua, Z.-C., Yang, M., Kumata, K., Hatori, A., et al. (2011) · Journal of Nuclear Medicine · doi:10.2967/jnumed.110.081588 · Cited by 32
Baines, A., & Gull, K. (2008) · Protist · doi:10.1016/j.protis.2007.09.001 · Cited by 32
“C2 domains are often Ca2+- dependent membrane targeting domains found in many proteins with a role in signal transduction or membrane trafficking (Davletov and Sudhof 1993).”
BackgroundFukuda, M., Katayama, E., & Mikoshiba, K. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m201697200 · Cited by 32
Synaptotagmin IV overexpression inhibits depolarization‐induced exocytosis in PC12 cells
Machado, H. B., Liu, W., Vician, L., & Herschman, H. (2004) · Journal of Neuroscience Research · doi:10.1002/jnr.20072 · Cited by 31
Regulation of phospholipase C-γ1 by the actin-regulatory protein villin
Panebra, A., Ma, S., Zhai, L.-W., Wang, X.-T., Rhee, S. G., & Khurana, S. (2001) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.2001.281.3.c1046 · Cited by 34
Interaction of Synaptotagmin with Lipid Bilayers, Analyzed by Single-Molecule Force Spectroscopy
Takahashi, H., Shahin, V., Henderson, R. M., Takeyasu, K., & Edwardson, J. M. (2010) · Biophysical Journal · doi:10.1016/j.bpj.2010.08.047 · Cited by 30
Targeted Molecular Imaging in Oncology: Focus on Radiation Therapy
Nimmagadda, S., Ford, E. C., Wong, J. W., & Pomper, M. G. (2008) · Seminars in Radiation Oncology · doi:10.1016/j.semradonc.2007.10.009 · Cited by 28
Mechanisms of Neurotransmitter Release
Littleton, J. T., Pallanck, L. J., & Ganetzky, B. (1999) · International review of neurobiology · doi:10.1016/s0074-7742(08)60544-9 · Cited by 24
Mehta, N., Mondal, S., Watson, E. T., Cui, Q., & Chapman, E. R. (2024) · Nature Communications · doi:10.1038/s41467-023-44414-5 · Cited by 28
“As a result, since the early 1990s, most biochemical studies made use of a truncated form of the protein, lacking the N-terminal region of the cytoplasmic domain (residues 80 – 95) 29 .”
Cellulose synthase interacting protein
Gu, Y., & Somerville, C. (2010) · Plant Signalling & Behavior · doi:10.4161/psb.5.12.13621 · Cited by 28
Cross-linking of Phospholipid Membranes is a Conserved Property of Calcium-sensitive Synaptotagmins
Connell, E., Giniatullina, A., Lai‐Kee‐Him, J., Tavaré, R., Ferrari, E., Roseman, A. M., Cojoc, D., Brisson, A. R., & Davletov, B. A. (2008) · Journal of Molecular Biology · doi:10.1016/j.jmb.2008.01.084 · Cited by 27
Self-citationVerhage, M., Hens, J. J., de Graan, P. D., Boomsma, F., Wiegant, V., da Silva, F. L., Gispen, W., & Ghijsen, W. (1995) · European Journal of Pharmacology · doi:10.1016/0922-4106(95)90081-0 · Cited by 28
Kannan, M., Riekhof, W. R., & Voelker, D. R. (2014) · Traffic · doi:10.1111/tra.12236 · Cited by 36
“Most characterized C2 domains are Ca2+-dependent phospholipid-binding modules that participate in protein–phospholipid and protein–protein interactions (45,46).”
BackgroundDirect, Ca2+-dependent Interaction between Tubulin and Synaptotagmin I
Honda, A., Yamada, M., Saisu, H., Takahashi, H., Mori, K. J., & Abe, T. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m112080200 · Cited by 27
Millet, Ó., Bernadó, P., Garcia, J. M., Rizo, J., & Pons, M. (2002) · FEBS Letters · doi:10.1016/s0014-5793(02)02508-5 · Cited by 27
Mapping the site of interaction between annexin VI and the p120GAP C2 domain
Chow, A., & Gawler, D. (1999) · FEBS Letters · doi:10.1016/s0014-5793(99)01336-8 · Cited by 27
Gerber, S. H., Rizo, J., & Südhof, T. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.c100108200 · Cited by 26
Self-citationImmature olfactory sensory neurons provide complementary input in the healthy olfactory system
Gregory, J. D., Herzog, R. S., Curtis, K. A., Marar, M. I., & Cheetham, C. E. (2025) · bioRxiv · doi:10.1007/978-4-431-55166-9 · Cited by 25
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Modulation of human α-synuclein aggregation by a combined effect of calcium and dopamine.
Jain, M., & Bhat, R. (2014) · Neurobiology of Disease · doi:10.1016/j.nbd.2013.11.004 · Cited by 25
The Role of C2 Domains in Ca2+-activated and Ca2+-independent Protein Kinase Cs in Aplysia*
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Function of Drosophila Synaptotagmins in membrane trafficking at synapses
Quiñones-Frías, M. C., & Littleton, J. T. (2021) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-021-03788-9 · Cited by 23
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Real-time assay for monitoring membrane association of lipid-binding domains
Connell, E., Scott, P., & Davletov, B. A. (2008) · Analytical Biochemistry · doi:10.1016/j.ab.2008.02.016 · Cited by 18
“Our turbidity data are in good agreement with the previously published characteristics of C2A [10,28], thus validating the assay for future studies of protein–membrane association.”
MethodInfluentialSelf-citationSynaptotagmin I and Ca 2+ promote half fusion more than full fusion in SNARE‐mediated bilayer fusion
Lu, X., Xu, Y., Zhang, F., & Shin, Y. (2006) · FEBS Letters · doi:10.1016/j.febslet.2006.03.035 · Cited by 25
Structural characterization of the C2 domain of novel protein kinase Cepsilon.
García-García, J., Gomez-Fernandez, J., & Corbalán-García, S. (2001) · European Journal of Biochemistry · doi:10.1046/j.1432-1327.2001.2680041107.x · Cited by 24
Drosophila AD3 mutation of synaptotagmin impairs calcium‐dependent self‐oligomerization activity
Fukuda, M., Kabayama, H., & Mikoshiba, K. (2000) · FEBS Letters · doi:10.1016/s0014-5793(00)02064-0 · Cited by 24
Metadata
- Authors
- Davletov, B. A., & Südhof, T. C.
- Affiliations
- Howard Hughes Medical Institute (US)
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 1993-12
- Volume
- 268
- Issue
- 35
- Pages
- 26386-26390
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W1591133722
- Cited by
- 480
- References
- 0
- Citations by year
- 2026: 2 · 2025: 7 · 2024: 8 · 2023: 6 · 2022: 12 · 2021: 5 · 2020: 4 · 2019: 8 · 2018: 9 · 2017: 6 · 2016: 6 · 2015: 12 · 2014: 21 · 2013: 11 · 2012: 9
- FWCI
- 9.29
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- 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 › Protein Kinase Regulation and GTPase Signaling
- Keywords
- synaptotagmin-1, C2 domain, calcium binding, phospholipid binding, cooperative binding, synaptic vesicle exocytosis, neurotransmitter release, synaptic vesicles, protein folding
- MeSH terms
- Amino Acid Sequence, Animals, Base Sequence, Binding Sites, Calcium, Calcium-Binding Proteins, Carbon, Enzyme Activation, Membrane Glycoproteins, Molecular Sequence Data, Nerve Tissue Proteins, Phospholipids, Protein Kinase C, DNA Primers, Synaptotagmins, Synaptotagmin I, Rats
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