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Crystal Structure of the Cytosolic C2A-C2B Domains of Synaptotagmin III: Implications for Ca+2-independent SNARE Complex Interaction

Journal Article · · Journal of Cell Biology
 [1];  [2];  [2]
  1. Yale Univ., New Haven, CT (United States); DOE/OSTI
  2. Yale Univ., New Haven, CT (United States)
+ Show Author Affiliations

Synaptotagmins are synaptic vesicle-associated, phospholipid-binding proteins most commonly associated with Ca+2-dependent exocytotic and Ca+2- independent endocytotic events. Synaptotagmin III is a 63.2-kD member of the synaptotagmin homology group; one of its characteristic properties is the ability to bind divalent cations and accessory proteins promiscuously. In the cytosolic portion of this protein, a flexible seven–amino acid linker joins two homologous C2 domains. The C2A domain binds to phospholipid membranes and other accessory proteins in a divalent cation-dependent fashion. The C2B domain promotes binding to other C2B domains, as well as accessory proteins independent of divalent cations. The 3.2 Å crystal structure of synaptotagmin III, residues 295–566, which includes the C2A and C2B domains, exhibits differences in the shape of the Ca+2-binding pocket, the electrostatic surface potential, and the stoichiometry of bound divalent cations for the two domains. These observations may explain the disparate binding properties of the two domains. The C2A and the C2B domains do not interact; synaptotagmin, therefore, covalently links two independent C2 domains, each with potentially different binding partners. A model of synaptotagmin's involvement in Ca+2-dependent regulation of membrane fusion through its interaction with the SNARE complex is presented in this article.

Research Organization:
Yale Univ., New Haven, CT (United States)
Sponsoring Organization:
USDOE Office of Science (SC), Biological and Environmental Research (BER). Biological Systems Science Division; National Institutes of Health (NIH); National Center for Research Resources (NCRR); National Science Foundation (NSF)
OSTI ID:
1625115
Journal Information:
Journal of Cell Biology, Journal Name: Journal of Cell Biology Journal Issue: 3 Vol. 147; ISSN 0021-9525
Publisher:
Rockefeller University PressCopyright Statement
Country of Publication:
United States
Language:
English

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Cited By (40)

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A Novel All Helix Fold of the AP180 Amino-Terminal Domain for Phosphoinositide Binding and Clathrin Assembly in Synaptic Vesicle Endocytosis journal February 2001
Rabphilin 3A retains NMDA receptors at synaptic sites through interaction with GluN2A/PSD-95 complex journal December 2015
Different states of synaptotagmin regulate evoked versus spontaneous release journal March 2016
Linker mutations reveal the complexity of synaptotagmin 1 action during synaptic transmission journal March 2014
Single-molecule FRET–derived model of the synaptotagmin 1–SNARE fusion complex journal February 2010
Molecular mechanism of the synaptotagmin–SNARE interaction in Ca2+-triggered vesicle fusion journal February 2010
Synaptotagmin-1 may be a distance regulator acting upstream of SNARE nucleation journal June 2011
The C2b Domain of Synaptotagmin Is a Ca2+–Sensing Module Essential for Exocytosis journal September 2000
The tandem C2 domains of synaptotagmin contain redundant Ca2+ binding sites that cooperate to engage t-SNAREs and trigger exocytosis journal September 2001
Mechanism of botulinum neurotoxin B and G entry into hippocampal neurons journal December 2007
Functional analysis of the interface between the tandem C2 domains of synaptotagmin-1 journal March 2016
Dynamic Control of Ca2+ Binding in the C2 Domains of Synaptotagmin 1 journal September 2018
A manual collection of Syt, Esyt, Rph3a, Rph3al, Doc2, and Dblc2 genes from 46 metazoan genomes - an open access resource for neuroscience and evolutionary biology journal January 2010
Synaptotagmin gene content of the sequenced genomes journal July 2004
Diagnostic film dosimeter in the study of radiation exposure to the population resulting from X-ray fiuoroscopy journal February 1968
Drosophila studies support a role for a presynaptic synaptotagmin mutation in a human congenital myasthenic syndrome journal September 2017
The C2A domain of synaptotagmin is an essential component of the calcium sensor for synaptic transmission journal February 2020
DOC2B Acts as a Calcium Switch and Enhances Vesicle Fusion journal July 2008
Synaptotagmin I is involved in the regulation of cortical granule exocytosis in the sea urchin journal January 2006
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Molecular Mechanism of the Synaptotagmin-Snare Interaction in Ca2+-Triggered Vesicle Fusion journal January 2010
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Phox domain interaction with PtdIns(3)P targets the Vam7 t-SNARE to vacuole membranes journal May 2001
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High Resolution Structure, Stability, and Synaptotagmin Binding of a Truncated Neuronal SNARE Complex journal December 2002
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Analysis of the Synaptotagmin Family during Reconstituted Membrane Fusion journal August 2008
A mutually induced conformational fit underlies Ca2+-directed interactions between calmodulin and the proximal C terminus of KCNQ4 K+ channels journal April 2019
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Related Subjects

59 BASIC BIOLOGICAL SCIENCES
C2 domains
SNARE
calcium-binding protein
cell biology
crystallography
synaptotagmin