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  Structure/function analysis of Ca2+ binding to the C(2)A domain of synaptotagmin 1

Fernandez-Chacon, R., Shin, O. H., Koenigstorfer, A., Matos, M. F., Meyer, A. C., Garcia, J., et al. (2002). Structure/function analysis of Ca2+ binding to the C(2)A domain of synaptotagmin 1. Journal of Neuroscience, 22(19), 8438-8446. Retrieved from http://www.jneurosci.org/cgi/reprint/22/19/8438.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-0012-F2D0-2 Version Permalink: http://hdl.handle.net/11858/00-001M-0000-0027-E46A-B
Genre: Journal Article

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 Creators:
Fernandez-Chacon, R.1, Author              
Shin, O. H., Author
Koenigstorfer, A., Author
Matos, M. F., Author
Meyer, A. C.1, Author              
Garcia, J., Author
Gerber, S. H., Author
Rizo, J., Author
Suedhof, T. C., Author
Rosenmund, C.1, Author              
Affiliations:
1Department of Membrane Biophysics, MPI for biophysical chemistry, Max Planck Society, ou_578579              

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Free keywords: synaptotagmin; neurotransmitter release; exocytosis; C2 domain; Ca2+-binding site; synaptic plasticity
 Abstract: Synaptotagmin 1, a Ca2+ sensor for fast synaptic vesicle exocytosis, contains two C-2 domains that form Ca2+-dependent complexes with phospholipids. To examine the functional importance of Ca2+ binding to the C(2)A domain of synaptotagmin 1, we studied two C(2)A domain mutations, D232N and D238N, using recombinant proteins and knock-in mice. Both mutations severely decreased intrinsic Ca2+ binding and Ca2+ dependent phospholipid binding by the isolated C(2)A domain. Both mutations, however, did not alter the apparent Ca2+ affinity of the double C-2 domain fragment, although both decreased the tightness of the Ca2+/phospholipid/double C-2 domain complex. When introduced into the endogenous synaptotagmin 1 gene in mice, the D232N and D238N mutations had no apparent effect on morbidity and mortality and caused no detectable alteration in the Ca2+-dependent properties of synaptotagmin 1. Electrophysiological recordings of cultured hippocampal neurons from knock-in mice revealed that neither mutation induced major changes in synaptic transmission. The D232N mutation, however, caused increased synaptic depression during repetitive stimulation, whereas the D238N mutation did not exhibit this phenotype. Our data indicate that Ca2+ binding to the C(2)A domain of synaptotagmin 1 may be important but not essential, consistent with the finding that the two C-2 domains cooperate and may be partially redundant in Ca2+ dependent phospholipid binding. Moreover, although the apparent Ca2+ affinity of the synaptotagmin 1/phospholipid complex is critical, the tightness of the Ca2+/phospholipid complex is not. Our data also demonstrate that subtle changes in the biochemical properties of synaptotagmin 1 can result in significant alterations in synaptic responses.

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Language(s): eng - English
 Dates: 2002-10-01
 Publication Status: Published in print
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Method: Peer
 Degree: -

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Title: Journal of Neuroscience
Source Genre: Journal
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Affiliations:
Publ. Info: -
Pages: - Volume / Issue: 22 (19) Sequence Number: - Start / End Page: 8438 - 8446 Identifier: -