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Rapid and selective binding to the synaptic SNARE complex suggests a modulatory role of complexins in neuroexocytosis

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Pabst,  S.
Department of Neurobiology, MPI for biophysical chemistry, Max Planck Society;

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Margittai,  M.
Department of Neurobiology, MPI for biophysical chemistry, Max Planck Society;

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Vainius,  D.
Department of Molecular Biology, MPI for biophysical chemistry, Max Planck Society;

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Jahn,  R.
Department of Neurobiology, MPI for biophysical chemistry, Max Planck Society;

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Fasshauer,  D.
Research Group of Structural Biochemistry, MPI for biophysical chemistry, Max Planck Society;

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599667.pdf
(Publisher version), 1022KB

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Citation

Pabst, S., Margittai, M., Vainius, D., Langen, R., Jahn, R., & Fasshauer, D. (2002). Rapid and selective binding to the synaptic SNARE complex suggests a modulatory role of complexins in neuroexocytosis. Journal of Biological Chemistry, 277(10), 7838-7848. Retrieved from http://www.jbc.org/content/277/10/7838.full.pdf+html.


Cite as: http://hdl.handle.net/11858/00-001M-0000-0012-F415-9
Abstract
The Ca2+ -triggered release of neurotransmitters is mediated by fusion of synaptic vesicles with the plasma membrane. The molecular machinery that translates the Ca2+ signal into exocytosis is only beginning to emerge. The soluble N- ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins syntaxin, SNAP-25, and synaptobrevin are central components of the fusion apparatus. Assembly of a membrane-bridging ternary SNARE complex is thought to initiate membrane merger, but the roles of other factors are less understood. Complexins are two highly conserved proteins that modulate the Ca2+ responsiveness of neurotransmitter release. In vitro, they bind in a 1:1 stoichiometry to the assembled synaptic SNARE complex, making complexins attractive candidates for controlling the exocytotic fusion apparatus. We have now performed a detailed structural, kinetic, and thermodynamic analysis of complexin binding to the SNARE complex. We found that no major conformational changes occur upon binding and that the complexin helix is aligned antiparallel to the four- helix bundle of the SNARE complex. Complexins bound rapidly (approximate to5 X 10(7) M-1 S-1) and with high affinity (approximate to10 nM), making it one of the fastest protein- protein interactions characterized so far in membrane trafficking. Interestingly, neither affinity nor binding kinetics was substantially altered by Ca2+ ions. No interaction of complexins was detectable either with individual SNARE proteins or with the binary syntaxin.SNAP-25 complex. Furthermore, complexin did not promote the formation of SNARE complex oligomers. Together, our data suggest that complexins modulate neuroexocytosis after assembly of membrane-bridging SNARE complexes.