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

Kyle Daniel Brewer, Taulant Bacaj, Andrea Cavalli, Carlo Camilloni, James David Swarbrick, Jin Liu, Amy Zhou, Peng Zhou, Nicholas Barlow, Junjie Xu, Alpay Burak Seven, Eric A Prinslow, Rashmi Voleti, Daniel Haussinger, Alexandre M J J Bonvin, Diana R Tomchick, Michele Vendruscolo, Bimbil Graham, Thomas C Sudhof, Josep Rizo

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82 Citations (Scopus)

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 ?-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
Pages (from-to)555 - 564
Number of pages10
JournalNature Structural & Molecular Biology
Volume22
Issue number7
DOIs
Publication statusPublished - 2015

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