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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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Self-citationCalcium-sensitive Phospholipid Binding Properties of Normal and Mutant Ferlin C2 Domains*
Davis, D., Doherty, K. R., Delmonte, A. J., & McNally, E. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m201858200 · Cited by 196
Apoptosis-detecting radioligands: current state of the art and future perspectives
Lahorte, C., Vanderheyden, J., Steinmetz, N. D., de Wiele, C. V., Dierckx, R. A. J. O., & Slegers, G. (2004) · European Journal of Nuclear Medicine and Molecular Imaging · doi:10.1007/s00259-004-1555-4 · Cited by 195
A molecular machine for neurotransmitter release: synaptotagmin and beyond
Südhof, T. C. (2013) · Nature Medicine · doi:10.1038/nm.3338 · Cited by 213
Self-citationE-Syts, a family of membranous Ca 2+ -sensor proteins with multiple C 2 domains
Min, S., Chang, W.-P., & Südhof, T. C. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0611725104 · Cited by 187
Self-citationA Novel Function for the Second C2 Domain of Synaptotagmin
Chapman, E. R., An, S. J., Edwardson, J., & Jahn, R. (1996) · Journal of Biological Chemistry · doi:10.1074/jbc.271.10.5844 · Cited by 191
“Previous work has shown that these effectors include negatively charged phospholipids (Brose et al., 1992; Davletov and Südhof, 1993; Chapman and Jahn, 1994) and syntaxin (Chapman et al., 1995; Li et al., 1995).”
BackgroundChapman, E., Desai, R. C., Davis, A. F., & Tornehl, C. K. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.49.32966 · Cited by 188
The Biochemistry of Neurotransmitter Secretion(*)
Bajjalieh, S., & Scheller, R. (1995) · Journal of Biological Chemistry · doi:10.1074/jbc.270.5.1971 · Cited by 188
Schulze, K., Littleton, J., Salzberg, A., Halachmi, N., Stern, M., Lev, Z., & Bellen, H. J. (1994) · Neuron · doi:10.1016/0896-6273(94)90048-5 · Cited by 188
Myoferlin, a candidate gene and potential modifier of muscular dystrophy.
Davis, D. B., Delmonte, A. J., Ly, C. T., & Mcnally, E. M. (2000) · Human Molecular Genetics · doi:10.1093/hmg/9.2.217 · Cited by 186
“C2 domains are known to bind Ca 2+, phospholipids and lipid bilayers (17), as well as other protei in Ca2+-dependent and -independent interactions (18).”
Batista, R., Saibo, N. J. M., Lourenço, T. F., & Oliveira, M. M. (2008) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.0707881105 · Cited by 179
“involved in signal transduction or membrane trafficking and thought to be involved in binding calcium-dependent phospholipids (21).”
BackgroundMolecular determinants of regulated exocytosis.
Gerber, S. H., & Südhof, T. (2002) · Diabetes · doi:10.2337/diabetes.51.2007.s3 · Cited by 179
Self-citationMolecular Heterogeneity of Phospholipase D (PLD)
Qin, W., Pappan, K., & Wang, X.-M. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.45.28267 · Cited by 179
Basel-Vanagaite, L., Attia, R., Yahav, M., Ferland, R. J., Anteki, L., Walsh, C. A., Olender, T., Straussberg, R., Magal, N., Taub, E., et al. (2005) · Journal of Medical Genetics · doi:10.1136/jmg.2005.035709 · Cited by 176
The Molecular Machinery of Neurotransmitter Release (Nobel Lecture)
Südhof, T. C. (2014) · Angewandte Chemie International Edition · doi:10.1002/anie.201406359 · Cited by 196
Self-citationIdentification of Novel Human WW Domain-containing Proteins by Cloning of Ligand Targets*
Pirozzi, G., Mcconnell, S., Uveges, A., Carter, J., Sparks, A., Kay, B. K., & Fowlkes, D. M. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.23.14611 · Cited by 171
Hammarberg, T., Provost, P., Persson, B., & Rådmark, O. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m006136200 · Cited by 165
Phosphatidylserine Decarboxylase 2 of Saccharomyces cerevisiáe
Trotter, P. J., Pedretti, J., Yates, R. O., & Voelker, D. (1995) · Journal of Biological Chemistry · doi:10.1074/jbc.270.11.6071 · Cited by 163
Apical Membrane Targeting of Nedd4 Is Mediated by an Association of Its C2 Domain with Annexin Xiiib
Plant, P., Lafont, F., Lecat, S., Verkade, P., Simons, K., & Rotin, D. (2000) · Journal of Cell Biology · doi:10.1083/jcb.149.7.1473 · Cited by 162
“Moreover, our work has shown a lack of preference of the Nedd4-C2 domain towards charged phospholipids (Plant et al., 1997), clearly dissimilar to several other C2 domains (Davletov and Sudhof, 1993; Yamaguchi et al., 1993; Chapman and Jahn, 1994; Gawler et al., 1995).”
BackgroundMolecular Mechanisms of Fast Neurotransmitter Release
Brünger, A. T., Choi, U. B., Lai, Y., Leitz, J., & Zhou, Q. (2018) · Annual Review of Biophysics · doi:10.1146/annurev-biophys-070816-034117 · Cited by 180
“Syt1 interacts with anionic membranes and SNARE complexes in both Ca2+-dependent and Ca2+-independent manners (7, 15, 16, 22, 27, 32, 42, 61, 75, 79, 114, 156, 160, 188).”
Functional Diversity of C2 Domains of Synaptotagmin Family
Fukuda, M., Kojima, T., Aruga, J., Niinobe, M., & Mikoshiba, K. (1995) · Journal of Biological Chemistry · doi:10.1074/jbc.270.44.26523 · Cited by 161
Triggered Ca2+ influx is required for extended synaptotagmin 1‐induced ER‐plasma membrane tethering
Idevall-Hagren, O., Lu, A., Xie, B.-C., & Camilli, P. D. (2015) · EMBO Journal · doi:10.15252/embj.201591565 · Cited by 160
“The approximately 2 l M EC 50 value for the Ca 2+ -dependent recruitment of E-Syt1 to the PM is in the same range of EC 50 values reported for the Ca 2+ -dependent binding of classical synaptotagmin 1 to acidic phospholipids (Davletov & Sudhof, 1993; Sugita et al , 2002; Shin et al , 2009) .”
Doc2 supports spontaneous synaptic transmission by a Ca2+-independent mechanism
Pang, Z., Bacaj, T., Yang, X., Zhou, P., Xu, W., & Südhof, T. (2011) · Neuron · doi:10.1016/j.neuron.2011.03.011 · Cited by 157
Self-citationSphingosine Facilitates SNARE Complex Assembly and Activates Synaptic Vesicle Exocytosis
Darios, F., Wasser, C. R., Shakirzyanova, A., Giniatullin, A., Goodman, K., Muñoz-Bravo, J. L., Raingo, J., Jorgačevski, J., Kreft, M., Zorec, R., et al. (2009) · Neuron · doi:10.1016/j.neuron.2009.04.024 · Cited by 157
“We analyzed whether sphingosine could compromise the ability of the cytoplasmic domain of synaptobrevin (aa 1–96) to bind fluorescently-labeled phospholipid liposomes in a standard pull-down procedure (Davletov and Sudhof, 1993).”
InfluentialSelf-citationHurley, J. H. (2006) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/j.bbalip.2006.02.020 · Cited by 158
“This region corresponds directly to the C2 structural domain that binds to Ca2+ in isolation, as shown first for another C2 domain protein, synaptotagmin I [4].”
BackgroundAugmenting neurotransmitter release by enhancing the apparent Ca 2+ affinity of synaptotagmin 1
Rhee, J.-S., Li, L. Y., Shin, O.-H., Rah, J.-C., Rizo, J., Südhof, T. C., & Rosenmund, C. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0509153102 · Cited by 155
Self-citationProtein–Protein and Protein–Membrane Associations in the Lignin Pathway
Bassard, J.-É., Richert, L., Geerinck, J., Renault, H., Duval, F., Ullmann, P., Schmitt, M., Meyer, E. H., Mutterer, J., Boerjan, W., et al. (2012) · The Plant Cell · doi:10.1105/tpc.112.102566 · Cited by 152
“…molecular weight protein complexes in mammalian cells (Browman et al., 2006; Hoegg et al., 2009) and two proteins containing a C2-domain (At1g51570 and SYTA) that is thought to be involved in calcium-dependent phospholipid binding and in membrane targeting processes (Davletov and Südhof, 1993).”
Background
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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