@article{ac9ad3f511c24060b5b91aada179c2c1,
title = "Dynamic binding mode of a Synaptotagmin-1-SNARE complex in solution",
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.",
author = "Brewer, {Kyle D.} and Taulant Bacaj and Andrea Cavalli and Carlo Camilloni and Swarbrick, {James D.} and Jin Liu and Amy Zhou and Peng Zhou and Nicholas Barlow and Junjie Xu and Seven, {Alpay B.} and Prinslow, {Eric A.} and Rashmi Voleti and Daniel H{\"a}ussinger and Bonvin, {Alexandre M.J.J.} and Tomchick, {Diana R.} and Michele Vendruscolo and Bim Graham and S{\"u}dhof, {Thomas C.} and Josep Rizo",
note = "Funding Information: We thank L. Kay for fruitful discussions and F. Peters (Max Planck Institute for Biophysical Chemistry) for generously providing a sample for Cys-Ph-TAHA– labeling. The DD2 console of one of the Agilent 600-MHz NMR spectrometers used for the research presented here was purchased with shared instrumentation grant S10RR026461 from the US National Institutes of Health (to M.K. Rosen; University of Texas Southwestern Medical Center). The authors acknowledge the Texas Advanced Computing Center at the University of Texas at Austin for providing high-performance computer resources that have contributed to the research results reported within this paper. This work was supported by Welch Foundation grant I-1304 (to J.R.), Australian Research Council (ARC) Discovery Grant DP150100383 (to B.G.), ARC Future Fellowship FT130100838 (to B.G.), Swiss National Science Foundation grant 200021_130263 (to D.H.) and US National Institutes of Health grants K99NS087086 (to T.B.) and NS040944 (to J.R.). Publisher Copyright: {\textcopyright} 2015 Nature America, Inc. All rights reserved.",
year = "2015",
month = jul,
day = "9",
doi = "10.1038/nsmb.3035",
language = "English",
volume = "22",
pages = "555--564",
journal = "Nature Structural and Molecular Biology",
issn = "1545-9993",
publisher = "Nature Publishing Group",
number = "7",
}