Cited by 480Cellular transport and secretionNeuroscience and Neuropharmacology ResearchProtein Kinase Regulation and GTPase Signaling

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A single C2 domain from synaptotagmin I is sufficient for high affinity Ca2+/phospholipid binding.

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Davletov, B A, Südhof, T C·1993·Journal of Biological Chemistry

DOI 10.1016/s0021-9258(19)74326-9

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Abstract

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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Müller, W. E., Custódio, M., Wiens, M., Zilberberg, C., Châtel, A., Müller, I., & Schröder, H. (2009) · doi:10.1007/978-90-481-2767-2_13 · Cited by 5
“The perforin-like protein contains one EGF-like domain cysteine pattern signature and a C2 domain [thought to be involved in Ca2+-dependent phospholipid binding (Davletov and Suedhof 1993).”
Role of the Membrane in the Modulation of the Activity of Protein Kinase C
Mosior, M., & Epand, R. (1999) · Journal of Liposome Research · doi:10.3109/08982109909044490 · Cited by 5
CK2 Phosphorylation Is Required for Regulation of Syntaxin 1A Activity in Ca2+-Triggered Release in Neuroendocrine Cells
Barak-Broner, N., Singer‐Lahat, D., Chikvashvili, D., & Lotan, I. (2020) · bioRxiv · doi:10.3390/ijms222413556 · Cited by 4
“…proteins involved in Ca2+-dependent exocytosis, including Syt-1, Syx, VAMP-2, and CAPS, are in vitro substrates of CK2, (Bennett et al., 1993; Davletov and Sudhof, 1993; Nielander et al., 1995; Nojiri et al., 2009), only the activity of CAPS has so far been shown to be dependent on CK2…”
Background
Localization of Rab3A-binding site on C2A domain of synaptotagmin I to reveal its regulatory mechanism.
Tang, X., Xie, C.-L., Wang, Y., & Wang, X.-C. (2017) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2016.12.074 · Cited by 4
Richard Scheller and Thomas Südhof receive the 2013 Albert Lasker Basic Medical Research Award.
Hurst, J. H. (2013) · Journal of Clinical Investigation · doi:10.1172/jci72681 · Cited by 4
“However, it wasn’t until 1990 that Südhof’s group purified the protein, cloned it, and determined that the cytoplasmic domain of p65 contained C2 regions, which exhibited sequence similarity to a region of PKC of unknown function.”
Volatile anaesthetic effects on phospholipid binding to synaptotagmin 1, a presynaptic Ca 2+ sensor
Fu, D., Vissavajjhala, P., & Hemmings, H. C. (2005) · British Journal of Anaesthesia · doi:10.1093/bja/aei163 · Cited by 4
The Molecular Mechanisms Underlying Synaptic Transmission
Ashery, U., Bielopolski, N., Lavi, A., Barak, B., Michaeli, L., Ben‐Simon, Y., Sheinin, A., Bar-On, D., Shapira, Z., & Gottfried, I. (2014) · Elsevier eBooks · doi:10.1016/b978-0-12-418675-0.00002-x · Cited by 13
Application of fluorescent probes to study mechanics and dynamics of Ca2+-triggered synaptotagmin C2 domain-membrane interactions.
Bai, J.-H., & Chapman, E. (2003) · Methods in Enzymology · doi:10.1016/s0076-6879(03)60113-8 · Cited by 4
Synaptotagmin II expression partially rescues the growth defect of the yeast sec15 secretory mutant
Damer, C. K., & Creutz, C. (1996) · Biology of the Cell · doi:10.1016/s0248-4900(97)86831-1 · Cited by 4
Membrane lipids couple synaptotagmin to SNARE-mediated granule fusion in insulin-secreting cells
Amos, C., Kiessling, V., Kreutzberger, A. J. B., Schenk, N. A., Mohan, R., Nyenhuis, S. B., Doyle, C. A., Wang, H., Levental, K. R., Levental, I., et al. (2023) · Molecular Biology of the Cell · doi:10.1091/mbc.e23-06-0225 · Cited by 7
“Syt1 binds Ca 2 + and phospholipids via its C2A and C2B domains (Davletov and Sudhof, 1993).”
Membrane-anchored calpains – hidden regulators of growth and development beyond plants?
Šafránek, M., Shumbusho, A., Johansen, W., Šarkanová, J., Voško, S., Bokor, B., Jásik, J., & Demko, V. (2023) · Frontiers in Plant Science · doi:10.3389/fpls.2023.1289785 · Cited by 3
Disruption of Leishmania flagellum attachment zone architecture causes flagellum loss
Halliday, C., de Liz, L. V., Vaughan, S., & Sunter, J. (2023) · Molecular Microbiology · doi:10.1111/mmi.15199 · Cited by 3
“Another domain, found in three proteins, CC2D, FAZ22 and FAZ35 (synaptogamin), was a C2 domain, which is important in calcium-binding and membrane-targeting processes (Davletov & Südhof, 1993; Zhou et al., 2011, 2018).”
Background
Pharmacological mechanism and structure of ubiquitin proteases associated with depression: A review.
Jiang, Y., Ye, L., Han, K.-X., Bao, L., Zhao, F., Wang, D., Li, X., Sun, Z.-M., & Chen, J. (2025) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2025.145220 · Cited by 2
Der molekulare Mechanismus der Neurotransmitterfreisetzung und Nervenzell‐Synapsen (Nobel‐Aufsatz)
Südhof, T. C. (2014) · Angewandte Chemie · doi:10.1002/ange.201406359 · Cited by 3
Self-citation
Vesicular Transport in the Secretory and Endocytic Pathways
Müsch, A. (2014) · Colloquium Series on Building Blocks of the Cell Cell Structure and Function · doi:10.4199/c0011ed1v01y201407bbc008 · Cited by 1
“region that allows the C2 domains to partially insert into the negatively charged membrane (Davletov and Sudhof, 1993; Perin et al., 1990).”
Background
C2-Domains in Ca2+-Signaling
Südhof, T. C., & Rizo, J. (2003) · Elsevier eBooks · doi:10.1016/b978-012124546-7/50500-3 · Cited by 3
Self-citation
Overview: Presynaptic Terminal Proteins Orchestrate Stepwise Synaptic Vesicle Phases
Mochida, S. (2014) · Springer eBooks · doi:10.1007/978-4-431-55166-9_1 · Cited by 2
“Studies on synaptotagmin-1 showed that C2 domains constitute autonomously folding Ca/phospholipid-binding domains (Perin et al. 1990; Davletov and Sudhof 1993; Sutton et al. 1995).”
Background
Structural characterization of the C2 domains of classical isozymes of protein kinase C and novel protein kinase Cε by using infrared spectroscopy
Corbalán-García, S., García-García, J., Sánchez-Carrillo, M., & Gomez-Fernandez, J. (2003) · doi:10.1155/2003/361563 · Cited by 2
“Pioneer studies with the C2A-domain of synaptotagmin I revealed that the C2 domain acts as a Ca2+ binding motif [6,48,63].”
Background
Calcium-sensitive synaptotagmin 11-lipid interaction modulates exo-endocytosis
Wu, X., Yao, J., Huo, J., Hu, S., Wang, B., Li, Z., Pei, Y., Fan, H., Zhan, S., Huang, R., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-67320-4 · Cited by 1
Dynamic Formation of the Protein-Lipid Pre-fusion Complex
Bykhovskaia, M. (2024) · bioRxiv · doi:10.1101/2024.04.17.589983 · Cited by 1
“The TM domain (TMD) of Syt1 fl was then inserted in the lipid bilayer mimicking SV, and all the lipid monomers overlapping with the TMD of Syt1 were removed (Fig.”
Method
Identification of a Novel Variant in CC2D1A Gene Linked to Autosomal Recessive Intellectual Disability 3 in an Iranian Family and Investigating the Structure and Pleiotropic Effects of this Gene
Rashvand, Z., Najmabadi, H., Kahrizi, K., Mozhdehipanah, H., Moradi, M., Estaki, Z., Taherkhani, K., Nikzat, N., Najafipour, R., & Omrani, M. (2024) · Iranian journal of child neurology · doi:10.22037/ijcn.v18i1.42188 · Cited by 1
A missense variant in MYOF is associated with ARVC and sudden cardiac death.
Xiao, J., Dong, Y., Jin, J., Yuan, Z., Wang, C., Xiang, R., & Guo, Y.-D. (2024) · Gene · doi:10.1016/j.gene.2024.148193 · Cited by 1
Quantitation of single action potential-evoked Ca2+ signals in CA1 pyramidal neuron presynaptic terminals
Church, E., Hamid, E., & Alford, S. (2018) · bioRxiv · doi:10.1101/337816 · Cited by 1
“Indeed, only one domain is necessary for membrane interaction (Davletov and Sudhof, 1993), although this low affinity increases on association with lipid membranes containing phosphatidylinositol 4,5-bisphosphate PI(4,5)P2 (Radhakrishnan et al.”
Background
Genetics of Hearing Loss
Mahdieh, N., Rabbani, B., & Inoue, I. (2012) · InTech eBooks · doi:10.5772/31984 · Cited by 1
“C2 domain is a structural domain in some proteins that are involved in directing proteins to the cell membrane [Davletov & Südhof, 1993].”
Background
A residue-level investigation of the equilibrium unfolding of the C2A domain of synaptotagmin 1.
Anbazhagan, V., Wang, H.-M., Lu, C.-S., & Yu, C. (2009) · Archives of Biochemistry and Biophysics · doi:10.1016/j.abb.2009.08.018 · Cited by 1
Role of synaptic proteins in neurotransmitter release-related vesicular trafficking
Lukyanetz, E. (2008) · Neurophysiology (New York) · doi:10.1007/s11062-008-9020-9 · Cited by 1
“The Ca2+ sensor function in exocytosis was supported by data indicating that synaptotagmin I bound Ca2+ in the presence of phospholipids with an exomicromolar affinity [40].”
Background
Screening, purification, and identification of annexin B1 mutants with high phosphatidylserine-binding activity and reduced immunogenicity
Wang, F., Luo, Q.-Y., He, Y., & Sun, S.-H. (2007) · Applied Microbiology and Biotechnology · doi:10.1007/s00253-007-0866-3 · Cited by 1
“It was reported that a single C2 domain from synaptotagmin I was sufficient for high affinity Ca-phospholipid binding (Davletov and Sudhof 1993), and recently, the Tc-labeled C2A domain of synaptotagmin was successfully used as a target-specific molecular probe for noninvasive imaging of acute myocar-”
Method
Synaptotagmin I-ΔC2B. A novel synaptotagmin isoform with a single C2 domain in the bovine adrenal medulla
Hewitt, E., Tao, J., Strasser, J. E., Cutler, D., & Dean, G. E. (2002) · doi:10.1016/s0005-2736(01)00459-x · Cited by 1
La machinerie moléculaire de sécrétion des neurotransmetteurs
Südhof, T. C. (2015) · Biologie Aujourd hui · doi:10.1051/jbio/2015012 · Cited by 2
Self-citation
Hetero-oligomerization of C2 domains of phospholipase C-related but catalytically inactive protein and synaptotagmin-1.
Wang, D.-G., Takeuchi, H., Gao, J., Zhang, Z., & Hirata, M. (2015) · Advances in Biological Regulation · doi:10.1016/j.jbior.2014.09.001 · Cited by 1
“…exert Ca2þ-dependent and independent molecular interactions, however, Syt1-C2A mediates Ca2þ-dependent phospholipid binding (Chapman and Jahn, 1994; Davletov and Sudhof, 1993) while Syt1-C2B mediates Ca2þ-independent interactions with AP-2, as well as b-SNAP (Schiavo et al., 1995), inositol…”
Synaptotagmin: Transducing Ca2+-Binding to Vesicle Fusion
Loewen, C. A., & Reist, N. E. (2008) · Humana Press eBooks · doi:10.1007/978-1-59745-481-0_6 · Cited by 1
Global Profiling of Lysine Ubiquitylation in the Human Hypothalamus
Zhang, Z., Ding, T., Kong, J., Wang, Q., Zhang, X., Shi, C., Yang, J., & Liu, J. (2025) · PROTEOMICS - CLINICAL APPLICATIONS · doi:10.1002/prca.70029
“Notably, except for PRKCB-K315, the other five conserved sites were located withintheC2domain(FigureS5B),aCa 2 + -dependentmembrane- targeting module widely involved in cellular signal transduction and membrane transport processes [28].”
The Extended Synaptotagmins of Physcomitrium patens
Kaier, A., & Ntefidou, M. (2025) · Plants · doi:10.3390/plants14071027
Molecular Evolution and Functional Characterization of PKC-α-like in Lamprey.
Liu, Z., Gao, Z., Lu, J.-L., Zhang, X.-Z., Ren, K., Li, X., Sun, F., Zhao, H., Li, Q.-W., Xu, Y., et al. (2025) · Fish and Shellfish Immunology · doi:10.1016/j.fsi.2025.110238
Genome-wide identification and characterization of multiple C2 domains and transmembrane region proteins in Gossypium hirsutum
Hao, P.-B., Wang, H.-T., Ma, L., Wu, A.-M., Chen, P.-Y., Cheng, S.-S., Wei, H.-L., & Yu, S.-X. (2020) · BMC Genomics · doi:10.1186/s12864-020-06842-1
Dynamic Control of Ca 2+ Binding in the C2 Domains of Synaptotagmin 1Preprint
Rock, P. J., Meyer, A. G., Evans, C. S., Chapman, E. R., & Sutton, R. B. (2018) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/412031
“Each C2 domain is an independently folded Ca-dependent phospholipid-binding domain composed of two β-sheets, each made up of four β-strands [12, 13].”
Background
Membrane Binding C2-Like Domains
Verdaguer, N., Corbalán-García, S., Ochoa, W., Gomez-Fernandez, J., & Fita, I. (2011) · doi:10.1002/9781119951438.eibc0515
Identification of a human cDNA clone that mediates adherence of pathogenic Neisseria to non-binding cells.
Jonsson, A.-B. (1998) · FEMS Microbiology Letters · doi:10.1111/j.1574-6968.1998.tb12974.x
“The C2 domain has been shown to bind membrane phospholipids in a calcium-dependent manner and is thought to function in the intracellular compartmentalization of proteins [23].”
Background

Authors: Davletov, B. A., & Südhof, T. C.
Affiliations: Howard Hughes Medical Institute (US)
ORCID: Davletov, B A
Südhof, T C
Venue: Journal of Biological Chemistry
Publisher: Elsevier BV
Published: 1993-12
Volume: 268
Issue: 35
Pages: 26386-26390
ISSN: 0021-9258 (ISSN-L)
DOI: 10.1016/s0021-9258(19)74326-9
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: cc-by
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
creativecommons.org/licenses/by/4.0/ (vor, 9808 d)
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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A single C2 domain from synaptotagmin I is sufficient for high affinity Ca2+/phospholipid binding.

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