Dynamic binding mode of a Synaptotagmin-1-SNARE complex in solution

Kyle D. Brewer, Taulant Bacaj, Andrea Cavalli, Carlo Camilloni, James D. Swarbrick, Jin Liu, Amy Zhou, Peng Zhou, Nicholas Barlow, Junjie Xu, Alpay B. Seven, Eric A. Prinslow, Rashmi Voleti, Daniel Häussinger, Alexandre M J J Bonvin, Diana R Tomchick, Michele Vendruscolo, Bim Graham, Thomas C. Südhof, Jose Rizo-Rey

Research output: Contribution to journalArticle

77 Scopus citations

Abstract

Rapid neurotransmitter release depends on the Ca 2+ sensor Synaptotagmin-1 (Syt1) and the SNARE complex formed by synaptobrevin, syntaxin-1 and SNAP-25. How Syt1 triggers release has been unclear, partly because elucidating high-resolution structures of Syt1-SNARE complexes has been challenging. An NMR approach based on lanthanide-induced pseudocontact shifts now reveals a dynamic binding mode in which basic residues in the concave side of the Syt1 C 2 B-domain β-sandwich interact with a polyacidic region of the SNARE complex formed by syntaxin-1 and SNAP-25. The physiological relevance of this dynamic structural model is supported by mutations in basic residues of Syt1 that markedly impair SNARE-complex binding in vitro and Syt1 function in neurons. Mutations with milder effects on binding have correspondingly milder effects on Syt1 function. Our results support a model whereby dynamic interaction facilitates cooperation between Syt1 and the SNAREs in inducing membrane fusion.

Original languageEnglish (US)
Pages (from-to)555-564
Number of pages10
JournalNature Structural and Molecular Biology
Volume22
Issue number7
DOIs
StatePublished - Jul 9 2015

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology

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    Brewer, K. D., Bacaj, T., Cavalli, A., Camilloni, C., Swarbrick, J. D., Liu, J., Zhou, A., Zhou, P., Barlow, N., Xu, J., Seven, A. B., Prinslow, E. A., Voleti, R., Häussinger, D., Bonvin, A. M. J. J., Tomchick, D. R., Vendruscolo, M., Graham, B., Südhof, T. C., & Rizo-Rey, J. (2015). Dynamic binding mode of a Synaptotagmin-1-SNARE complex in solution. Nature Structural and Molecular Biology, 22(7), 555-564. https://doi.org/10.1038/nsmb.3035