Dynamic binding mode of a Synaptotagmin-1-SNARE complex in solution
Brewer, Kyle D; Bacaj, Taulant; Cavalli, Andrea; Camilloni, Carlo; Swarbrick, James D; Liu, Jin; Zhou, Amy; Zhou, Peng; Barlow, Nicholas; Xu, Junjie; Seven, Alpay B; Prinslow, Eric A; Voleti, Rashmi; Häussinger, Daniel; Bonvin, Alexandre M J J; Tomchick, Diana R; Vendruscolo, Michele; Graham, Bim; Südhof, Thomas C; Rizo, Josep
(2015) Nature Structural and Molecular Biology, volume 22, issue 7, pp. 555 - 64
(Article)
Abstract
Rapid neurotransmitter release depends on the Ca2+ 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
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binding mode in which basic residues in the concave side of the Syt1 C2B-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.
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Keywords: Animals, Cells, Cultured, Humans, Mice, Inbred C57BL, Models, Molecular, Neurons, Nuclear Magnetic Resonance, Biomolecular, Protein Binding, Protein Structure, Tertiary, Rats, SNARE Proteins, Synaptotagmin I, Taverne
ISSN: 1545-9993
Publisher: Nature Publishing Group
(Peer reviewed)
