PDBsum entry 1byn

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Endocytosis/exocytosis PDB id
Jmol PyMol
Protein chain
128 a.a. *
_CA ×3
* Residue conservation analysis
PDB id:
Name: Endocytosis/exocytosis
Title: Solution structure of the calcium-bound first c2-domain of synaptotagmin i
Structure: Protein (synaptotagmin i). Chain: a. Fragment: c2a-domain. Engineered: yes
Source: Rattus norvegicus. Norway rat. Organism_taxid: 10116. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.
NMR struc: 20 models
Authors: X.Shao,I.Fernandez,T.C.Sudhof,J.Rizo
Key ref:
X.Shao et al. (1998). Solution structures of the Ca2+-free and Ca2+-bound C2A domain of synaptotagmin I: does Ca2+ induce a conformational change? Biochemistry, 37, 16106-16115. PubMed id: 9819203 DOI: 10.1021/bi981789h
18-Oct-98     Release date:   21-Oct-98    
Go to PROCHECK summary

Protein chain
Pfam   ArchSchema ?
P21707  (SYT1_RAT) -  Synaptotagmin-1
421 a.a.
128 a.a.
Key:    PfamA domain  PfamB domain  Secondary structure  CATH domain

 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     membrane   2 terms 
  Biological process     neurotransmitter secretion   1 term 
  Biochemical function     calcium-dependent phospholipid binding     1 term  


DOI no: 10.1021/bi981789h Biochemistry 37:16106-16115 (1998)
PubMed id: 9819203  
Solution structures of the Ca2+-free and Ca2+-bound C2A domain of synaptotagmin I: does Ca2+ induce a conformational change?
X.Shao, I.Fernandez, T.C.Südhof, J.Rizo.
C2 domains are widespread Ca2+-binding modules that are particularly abundant in proteins involved in membrane traffic and signal transduction. The C2A domain of synaptotagmin I is believed to play a key role in neurotransmitter release through its Ca2+-dependent interactions with syntaxin and phospholipids. Elucidating the structural consequences of Ca2+ binding to the C2A domain is critical for understanding its mechanism of action and for models of the functions of other C2 domains. We have determined the solution structure of the Ca2+-free and Ca2+-bound forms of the C2A domain of synaptotagmin I by NMR spectroscopy. Our data represent the first structure determination of a C2 domain in its Ca2+-free and Ca2+-bound forms. Three Ca2+ ions were included in the Ca2+-bound structure, yielding a Ca2+-binding motif that involves five aspartate side chains and one serine side chain. Ca2+ immobilizes the structure of the C2A domain but does not produce a significant conformational change from a well-defined conformation to another. Thus, the mechanism of action of the C2A domain of synaptotagmin I is different from that used by Ca2+-binding proteins of the EF-hand family. The main effect of Ca2+ binding on the C2A domain is to change its electrostatic potential rather than its structure. These results support a model whereby the C2A domain functions as an electrostatic switch in neurotransmitter release. The similarity between the structures of the synaptotagmin I C2A domain and the PLC-delta1 C2 domain suggests that the latter binds four Ca2+ ions and acts by a similar mechanism. This mechanism may also be valid for other C2 domains that share the unusual ability to bind multiple Ca2+ ions in a tight cluster at the tip of the domain.

Literature references that cite this PDB file's key reference

  PubMed id Reference
20921140 C.P.Johnson, and E.R.Chapman (2010).
Otoferlin is a calcium sensor that directly regulates SNARE-mediated membrane fusion.
  J Cell Biol, 191, 187-197.  
  20824061 M.Xue, T.K.Craig, O.H.Shin, L.Li, C.A.Brautigam, D.R.Tomchick, T.C.Südhof, C.Rosenmund, and J.Rizo (2010).
Structural and mutational analysis of functional differentiation between synaptotagmins-1 and -7.
  PLoS One, 5, 0.
PDB code: 3n5a
20154707 O.H.Shin, J.Lu, J.S.Rhee, D.R.Tomchick, Z.P.Pang, S.M.Wojcik, M.Camacho-Perez, N.Brose, M.Machius, J.Rizo, C.Rosenmund, and T.C.Südhof (2010).
Munc13 C2B domain is an activity-dependent Ca2+ regulator of synaptic exocytosis.
  Nat Struct Mol Biol, 17, 280-288.
PDB codes: 3kwt 3kwu
20173763 U.B.Choi, P.Strop, M.Vrljic, S.Chu, A.T.Brunger, and K.R.Weninger (2010).
Single-molecule FRET-derived model of the synaptotagmin 1-SNARE fusion complex.
  Nat Struct Mol Biol, 17, 318-324.  
20187120 V.Breukels, and G.W.Vuister (2010).
Binding of calcium is sensed structurally and dynamically throughout the second calcium-binding domain of the sodium/calcium exchanger.
  Proteins, 78, 1813-1824.  
20688915 Z.Wang, and E.R.Chapman (2010).
Rat and Drosophila synaptotagmin 4 have opposite effects during SNARE-catalyzed membrane fusion.
  J Biol Chem, 285, 30759-30766.  
20573977 Z.Zhang, E.Hui, E.R.Chapman, and M.B.Jackson (2010).
Regulation of exocytosis and fusion pores by synaptotagmin-effector interactions.
  Mol Biol Cell, 21, 2821-2831.  
19632983 A.Radhakrishnan, A.Stein, R.Jahn, and D.Fasshauer (2009).
The Ca2+ affinity of synaptotagmin 1 is markedly increased by a specific interaction of its C2B domain with phosphatidylinositol 4,5-bisphosphate.
  J Biol Chem, 284, 25749-25760.  
19501597 D.Z.Herrick, W.Kuo, H.Huang, C.D.Schwieters, J.F.Ellena, and D.S.Cafiso (2009).
Solution and membrane-bound conformations of the tandem C2A and C2B domains of synaptotagmin 1: Evidence for bilayer bridging.
  J Mol Biol, 390, 913-923.  
19703397 E.Hui, C.P.Johnson, J.Yao, F.M.Dunning, and E.R.Chapman (2009).
Synaptotagmin-mediated bending of the target membrane is a critical step in Ca(2+)-regulated fusion.
  Cell, 138, 709-721.  
18650324 B.E.Paddock, A.R.Striegel, E.Hui, E.R.Chapman, and N.E.Reist (2008).
Ca2+-dependent, phospholipid-binding residues of synaptotagmin are critical for excitation-secretion coupling in vivo.
  J Neurosci, 28, 7458-7466.  
18280495 E.Johnson, L.Bruschweiler-Li, S.A.Showalter, G.W.Vuister, F.Zhang, and R.Brüschweiler (2008).
Structure and dynamics of Ca2+-binding domain 1 of the Na+/Ca2+ exchanger in the presence and in the absence of Ca2+.
  J Mol Biol, 377, 945-955.  
18275379 E.R.Chapman (2008).
How does synaptotagmin trigger neurotransmitter release?
  Annu Rev Biochem, 77, 615-641.  
18956883 H.Huang, and D.S.Cafiso (2008).
Conformation and membrane position of the region linking the two C2 domains in synaptotagmin 1 by site-directed spin labeling.
  Biochemistry, 47, 12380-12388.  
18596818 J.Rizo, and C.Rosenmund (2008).
Synaptic vesicle fusion.
  Nat Struct Mol Biol, 15, 665-674.  
18618940 J.Rizo, and C.Rosenmund (2008).
Synaptic vesicle fusion.
  Nat Struct Mol Biol, 15, 665-674.  
18953334 M.Xue, C.Ma, T.K.Craig, C.Rosenmund, and J.Rizo (2008).
The Janus-faced nature of the C(2)B domain is fundamental for synaptotagmin-1 function.
  Nat Struct Mol Biol, 15, 1160-1168.  
18458823 X.Chen, J.Lu, I.Dulubova, and J.Rizo (2008).
NMR analysis of the closed conformation of syntaxin-1.
  J Biomol NMR, 41, 43-54.  
17767192 C.M.Carr, and M.Munson (2007).
Tag team action at the synapse.
  EMBO Rep, 8, 834-838.  
19404424 C.Schultz (2007).
Molecular tools for cell and systems biology.
  HFSP J, 1, 230-248.  
17320903 H.Dai, N.Shen, D.Araç, and J.Rizo (2007).
A quaternary SNARE-synaptotagmin-Ca2+-phospholipid complex in neurotransmitter release.
  J Mol Biol, 367, 848-863.  
17114221 J.A.Kertz, P.F.Almeida, A.A.Frazier, A.K.Berg, and A.Hinderliter (2007).
The cooperative response of synaptotagmin I C2A. A hypothesis for a Ca2+-driven molecular hammer.
  Biophys J, 92, 1409-1418.  
17914059 K.L.Lynch, R.R.Gerona, E.C.Larsen, R.F.Marcia, J.C.Mitchell, and T.F.Martin (2007).
Synaptotagmin C2A loop 2 mediates Ca2+-dependent SNARE interactions essential for Ca2+-triggered vesicle exocytosis.
  Mol Biol Cell, 18, 4957-4968.  
17565980 L.F.Cavanaugh, X.Chen, B.C.Richardson, D.Ungar, I.Pelczer, J.Rizo, and F.M.Hughson (2007).
Structural analysis of conserved oligomeric Golgi complex subunit 2.
  J Biol Chem, 282, 23418-23426.
PDB code: 2jqq
17478680 S.Martens, M.M.Kozlov, and H.T.McMahon (2007).
How synaptotagmin promotes membrane fusion.
  Science, 316, 1205-1208.  
17085504 S.Varma, and E.Jakobsson (2007).
The cPLA2 C2alpha domain in solution: structure and dynamics of its Ca2+-activated and cation-free states.
  Biophys J, 92, 966-976.  
16515538 A.J.Groffen, R.Friedrich, E.C.Brian, U.Ashery, and M.Verhage (2006).
DOC2A and DOC2B are sensors for neuronal activity with unique calcium-dependent and kinetic properties.
  J Neurochem, 97, 818-833.  
16491093 D.Araç, X.Chen, H.A.Khant, J.Ubach, S.J.Ludtke, M.Kikkawa, A.E.Johnson, W.Chiu, T.C.Südhof, and J.Rizo (2006).
Close membrane-membrane proximity induced by Ca(2+)-dependent multivalent binding of synaptotagmin-1 to phospholipids.
  Nat Struct Mol Biol, 13, 209-217.  
16698267 J.Rizo, X.Chen, and D.Araç (2006).
Unraveling the mechanisms of synaptotagmin and SNARE function in neurotransmitter release.
  Trends Cell Biol, 16, 339-350.  
16790935 M.Biadene, P.Montaville, G.M.Sheldrick, and S.Becker (2006).
Structure of the C2A domain of rabphilin-3A.
  Acta Crystallogr D Biol Crystallogr, 62, 793-799.
PDB code: 2chd
  16946482 M.Montes, K.L.Fuson, R.B.Sutton, and J.J.Robert (2006).
Purification, crystallization and X-ray diffraction analysis of human synaptotagmin 1 C2A-C2B.
  Acta Crystallogr Sect F Struct Biol Cryst Commun, 62, 926-929.  
15576364 I.Voskoboinik, M.C.Thia, J.Fletcher, A.Ciccone, K.Browne, M.J.Smyth, and J.A.Trapani (2005).
Calcium-dependent plasma membrane binding and cell lysis by perforin are mediated through its C2 domain: A critical role for aspartate residues 429, 435, 483, and 485 but not 491.
  J Biol Chem, 280, 8426-8434.  
16023350 J.Stetefeld, and M.A.Ruegg (2005).
Structural and functional diversity generated by alternative mRNA splicing.
  Trends Biochem Sci, 30, 515-521.  
15821166 M.E.Bowen, K.Weninger, J.Ernst, S.Chu, and A.T.Brunger (2005).
Single-molecule studies of synaptotagmin and complexin binding to the SNARE complex.
  Biophys J, 89, 690-702.  
15869386 W.Cho, and R.V.Stahelin (2005).
Membrane-protein interactions in cell signaling and membrane trafficking.
  Annu Rev Biophys Biomol Struct, 34, 119-151.  
15044740 C.H.Lee, J.W.Jung, A.Yee, C.H.Arrowsmith, and W.Lee (2004).
Solution structure of a novel calcium binding protein, MTH1880, from Methanobacterium thermoautotrophicum.
  Protein Sci, 13, 1148-1154.
PDB codes: 1iqo 1iqs
15311271 H.Dai, O.H.Shin, M.Machius, D.R.Tomchick, T.C.Südhof, and J.Rizo (2004).
Structural basis for the evolutionary inactivation of Ca2+ binding to synaptotagmin 4.
  Nat Struct Mol Biol, 11, 844-849.
PDB codes: 1w15 1w16
14718921 J.Bai, W.C.Tucker, and E.R.Chapman (2004).
PIP2 increases the speed of response of synaptotagmin and steers its membrane-penetration activity toward the plasma membrane.
  Nat Struct Mol Biol, 11, 36-44.  
14718922 J.Garcia, S.H.Gerber, S.Sugita, T.C.Südhof, and J.Rizo (2004).
A conformational switch in the Piccolo C2A domain regulated by alternative splicing.
  Nat Struct Mol Biol, 11, 45-53.
PDB code: 1rh8
13679516 J.H.Evans, S.H.Gerber, D.Murray, and C.C.Leslie (2004).
The calcium binding loops of the cytosolic phospholipase A2 C2 domain specify targeting to Golgi and ER in live cells.
  Mol Biol Cell, 15, 371-383.  
15340165 Y.Cheng, S.M.Sequeira, L.Malinina, V.Tereshko, T.H.Söllner, and D.J.Patel (2004).
Crystallographic identification of Ca2+ and Sr2+ coordination sites in synaptotagmin I C2B domain.
  Protein Sci, 13, 2665-2672.
PDB codes: 1tjm 1tjx 1uov 1uow
14529272 C.Y.Kim, Y.D.Koo, J.B.Jin, B.C.Moon, C.H.Kang, S.T.Kim, B.O.Park, S.Y.Lee, M.L.Kim, I.Hwang, K.Y.Kang, J.D.Bahk, S.Y.Lee, and M.J.Cho (2003).
Rice C2-domain proteins are induced and translocated to the plasma membrane in response to a fungal elicitor.
  Biochemistry, 42, 11625-11633.  
12948775 L.K.Tamm, J.Crane, and V.Kiessling (2003).
Membrane fusion: a structural perspective on the interplay of lipids and proteins.
  Curr Opin Struct Biol, 13, 453-466.  
12795692 N.Jarousse, J.D.Wilson, D.Arac, J.Rizo, and R.B.Kelly (2003).
Endocytosis of synaptotagmin 1 is mediated by a novel, tryptophan-containing motif.
  Traffic, 4, 468-478.  
12963743 P.Wang, C.T.Wang, J.Bai, M.B.Jackson, and E.R.Chapman (2003).
Mutations in the effector binding loops in the C2A and C2B domains of synaptotagmin I disrupt exocytosis in a nonadditive manner.
  J Biol Chem, 278, 47030-47037.  
12645522 R.Cohen, L.A.Elferink, and D.Atlas (2003).
The C2A domain of synaptotagmin alters the kinetics of voltage-gated Ca2+ channels Ca(v)1.2 (Lc-type) and Ca(v)2.3 (R-type).
  J Biol Chem, 278, 9258-9266.  
12531893 R.V.Stahelin, J.D.Rafter, S.Das, and W.Cho (2003).
The molecular basis of differential subcellular localization of C2 domains of protein kinase C-alpha and group IVa cytosolic phospholipase A2.
  J Biol Chem, 278, 12452-12460.  
12900172 T.W.Koh, and H.J.Bellen (2003).
Synaptotagmin I, a Ca2+ sensor for neurotransmitter release.
  Trends Neurosci, 26, 413-422.  
12578982 Y.Wu, Y.He, J.Bai, S.R.Ji, W.C.Tucker, E.R.Chapman, and S.F.Sui (2003).
Visualization of synaptotagmin I oligomers assembled onto lipid monolayers.
  Proc Natl Acad Sci U S A, 100, 2082-2087.  
12009889 A.A.Frazier, M.A.Wisner, N.J.Malmberg, K.G.Victor, G.E.Fanucci, E.A.Nalefski, J.J.Falke, and D.S.Cafiso (2002).
Membrane orientation and position of the C2 domain from cPLA2 by site-directed spin labeling.
  Biochemistry, 41, 6282-6292.  
11340056 A.T.Brunger (2001).
Structure of proteins involved in synaptic vesicle fusion in neurons.
  Annu Rev Biophys Biomol Struct, 30, 157-171.  
11297924 A.T.Brunger (2001).
Structural insights into the molecular mechanism of calcium-dependent vesicle-membrane fusion.
  Curr Opin Struct Biol, 11, 163-173.  
11517928 D.Reverter, S.Strobl, C.Fernandez-Catalan, H.Sorimachi, K.Suzuki, and W.Bode (2001).
Structural basis for possible calcium-induced activation mechanisms of calpains.
  Biol Chem, 382, 753-766.  
11317268 E.A.Fon, and R.H.Edwards (2001).
Molecular mechanisms of neurotransmitter release.
  Muscle Nerve, 24, 581-601.  
11258923 E.A.Nalefski, M.A.Wisner, J.Z.Chen, S.R.Sprang, M.Fukuda, K.Mikoshiba, and J.J.Falke (2001).
C2 domains from different Ca2+ signaling pathways display functional and mechanistic diversity.
  Biochemistry, 40, 3089-3100.  
11399430 G.J.Augustine (2001).
How does calcium trigger neurotransmitter release?
  Curr Opin Neurobiol, 11, 320-326.  
11413542 J.M.Mackler, and N.E.Reist (2001).
Mutations in the second C2 domain of synaptotagmin disrupt synaptic transmission at Drosophila neuromuscular junctions.
  J Comp Neurol, 436, 4.  
11352720 J.Ubach, Y.Lao, I.Fernandez, D.Arac, T.C.Südhof, and J.Rizo (2001).
The C2B domain of synaptotagmin I is a Ca2+-binding module.
  Biochemistry, 40, 5854-5860.  
11285225 S.H.Gerber, J.Garcia, J.Rizo, and T.C.Südhof (2001).
An unusual C(2)-domain in the active-zone protein piccolo: implications for Ca(2+) regulation of neurotransmitter release.
  EMBO J, 20, 1605-1619.  
10851178 A.T.Brunger (2000).
Structural insights into the molecular mechanism of Ca(2+)-dependent exocytosis.
  Curr Opin Neurobiol, 10, 293-302.  
10933784 B.Mehrotra, D.G.Myszka, and G.D.Prestwich (2000).
Binding kinetics and ligand specificity for the interactions of the C2B domain of synaptogmin II with inositol polyphosphates and phosphoinositides.
  Biochemistry, 39, 9679-9686.  
11208133 J.A.Ybe, D.E.Wakeham, F.M.Brodsky, and P.K.Hwang (2000).
Molecular structures of proteins involved in vesicle fusion.
  Traffic, 1, 474-479.  
10940243 J.H.Hurley, and S.Misra (2000).
Signaling and subcellular targeting by membrane-binding domains.
  Annu Rev Biophys Biomol Struct, 29, 49-79.  
11114503 K.M.Misura, A.P.May, and W.I.Weis (2000).
Protein-protein interactions in intracellular membrane fusion.
  Curr Opin Struct Biol, 10, 662-671.  
10811903 R.A.García, C.E.Forde, and H.A.Godwin (2000).
Calcium triggers an intramolecular association of the C2 domains in synaptotagmin.
  Proc Natl Acad Sci U S A, 97, 5883-5888.  
10639123 S.Strobl, C.Fernandez-Catalan, M.Braun, R.Huber, H.Masumoto, K.Nakagawa, A.Irie, H.Sorimachi, G.Bourenkow, H.Bartunik, K.Suzuki, and W.Bode (2000).
The crystal structure of calcium-free human m-calpain suggests an electrostatic switch mechanism for activation by calcium.
  Proc Natl Acad Sci U S A, 97, 588-592.
PDB codes: 1kfu 1kfx
10715114 S.Sugita, and T.C.Südhof (2000).
Specificity of Ca2+-dependent protein interactions mediated by the C2A domains of synaptotagmins.
  Biochemistry, 39, 2940-2949.  
10359764 A.Ball, R.Nielsen, M.H.Gelb, and B.H.Robinson (1999).
Interfacial membrane docking of cytosolic phospholipase A2 C2 domain using electrostatic potential-modulated spin relaxation magnetic resonance.
  Proc Natl Acad Sci U S A, 96, 6637-6642.  
10545502 R.B.Sutton, J.A.Ernst, and A.T.Brunger (1999).
Crystal structure of the cytosolic C2A-C2B domains of synaptotagmin III. Implications for Ca(+2)-independent snare complex interaction.
  J Cell Biol, 147, 589-598.
PDB code: 1dqv
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB code is shown on the right.