Dynamic binding mode of a Synaptotagmin-1-SNARE complex in solution
Files
Publication date
2015-07
Authors
Brewer, Kyle D
Bacaj, Taulant
Cavalli, Andrea
Camilloni, Carlo
Swarbrick, James D
Liu, Jin
Zhou, Amy
Zhou, Peng
Barlow, Nicholas
Xu, Junjie
Editors
Advisors
Supervisors
Document Type
Article
Metadata
Show full item recordCollections
License
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 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.
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
Citation
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, J 2015, 'Dynamic binding mode of a Synaptotagmin-1-SNARE complex in solution', Nature Structural and Molecular Biology, vol. 22, no. 7, pp. 555-64. https://doi.org/10.1038/nsmb.3035