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Cited by 131Cellular transport and secretionNeuroscience and Neuropharmacology ResearchLipid Membrane Structure and Behavior

The Janus-faced nature of the C2B domain is fundamental for synaptotagmin-1 function

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Xue, Mingshan, Ma, Cong, Craig, Timothy K, Rosenmund, Christian, Rizo, Josep·2008·Nature Structural & Molecular Biology
DOI 10.1038/nsmb.1508PMC PMC2587052
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Abstract

Synaptotagmin-1 functions as a Ca2+ sensor in neurotransmitter release and was proposed to act on both the synaptic vesicle and plasma membranes through interactions involving the Ca2+ binding top loops of its C(2) domains and the Ca2+-independent bottom face of the C(2)B domain. However, the functional importance of the C(2)B domain bottom face is unclear. We now show that mutating two conserved arginine residues at the C(2)B domain bottom face practically abolishes synchronous release in hippocampal neurons. Reconstitution experiments reveal that Ca2+-synaptotagmin-1 can dramatically stimulate the rate of SNARE-dependent lipid mixing, and that the two-arginine mutation strongly impairs this activity. These results demonstrate that synaptotagmin-1 function depends crucially on the bottom face of the C(2)B domain and strongly support the notion that synaptotagmin-1 triggers membrane fusion and neurotransmitter release by bringing the vesicle and plasma membranes together, much like the SNAREs do but in a Ca2+-dependent manner.

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  • Region I mutants retained some rescue ability, whereas region II mutants were nearly non-functional, including the R398Q, R399Q mutant.

    “Interestingly, the region I mutants retained some rescue ability, in contrast to region II mutants that were nearly non-functional (Figs. 4a, b), including the R398Q, R399Q mutant as previously reported36.”

    From Architecture of the synaptotagmin–SNARE machinery for neuronal exocytosis (2015) · cites this paper as [36]

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Authors
Xue, M., Ma, C., Craig, T. K., Rosenmund, C., & Rizo, J.
Affiliations
  • Baylor College of Medicine (US)
  • The University of Texas Southwestern Medical Center (US)
Corresponding author
  • Rosenmund, Christian
  • Rizo, Josep
ORCID
Venue
Nature Structural & Molecular Biology
Publisher
Springer Science and Business Media LLC
Published
2008-10-26
Volume
15
Issue
11
Pages
1160-1168
ISSN
  • 1545-9985 (ISSN-L)
  • 1545-9993
DOI
10.1038/nsmb.1508
PMC
PMC2587052
OpenAlex
W2076881120
Cited by
131
References
1
Citations by year
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FWCI
5.11
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature Structural & Molecular Biology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institute of General Medical Sciences (GM 65364, R01GM065364)
  • National Institute of Neurological Disorders and Stroke (NS40944, R01NS050655, NS50655, R01NS040944)
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 › Lipid Membrane Structure and Behavior
Keywords
synaptotagmin-1, C2B domain, C2A domain, Ca2+ binding, neurotransmitter release, synchronous release, hippocampal neurons, membrane fusion, synaptic vesicles, plasma membrane, arginine residues
MeSH terms
Amino Acid Sequence, Animals, Arginine, Calcium, Cell Membrane, Cells, Cultured, Hippocampus, Humans, Lipids, Membrane Fusion, Models, Molecular, Molecular Sequence Data, Mutation, Neurons, Sequence Alignment, Protein Structure, Tertiary, Mice, Knockout, Patch-Clamp Techniques, SNARE Proteins, Synaptotagmin I, Mice, Rats

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