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

doi:10.1038/nsmb.3035

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

Medicinal Chemistry

Research output: Contribution to journal › Article › Research › peer-review

126 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 language	English
Pages (from-to)	555 - 564
Number of pages	10
Journal	Nature Structural & Molecular Biology
Volume	22
Issue number	7
DOIs	https://doi.org/10.1038/nsmb.3035
Publication status	Published - 2015

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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., Haussinger, D., Bonvin, A. M. J. J., Tomchick, D. R., Vendruscolo, M., Graham, B., Sudhof, T. C., & Rizo, J. (2015). Dynamic binding mode of a Synaptotagmin-1-SNARE complex in solution. Nature Structural & Molecular Biology, 22(7), 555 - 564. https://doi.org/10.1038/nsmb.3035

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

year = "2015",

doi = "10.1038/nsmb.3035",

language = "English",

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journal = "Nature Structural \& Molecular Biology",

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Brewer, KD, Bacaj, T, Cavalli, A, Camilloni, C, Swarbrick, JD, Liu, J, Zhou, A, Zhou, P, Barlow, N, Xu, J, Seven, AB, Prinslow, EA, Voleti, R, Haussinger, D, Bonvin, AMJJ, Tomchick, DR, Vendruscolo, M, Graham, B, Sudhof, TC & Rizo, J 2015, 'Dynamic binding mode of a Synaptotagmin-1-SNARE complex in solution', Nature Structural & Molecular Biology, vol. 22, no. 7, pp. 555 - 564. https://doi.org/10.1038/nsmb.3035

TY - JOUR

T1 - Dynamic binding mode of a Synaptotagmin-1-SNARE complex in solution

AU - Brewer, Kyle Daniel

AU - Bacaj, Taulant

AU - Cavalli, Andrea

AU - Camilloni, Carlo

AU - Swarbrick, James David

AU - Liu, Jin

AU - Zhou, Amy

AU - Zhou, Peng

AU - Barlow, Nicholas

AU - Xu, Junjie

AU - Seven, Alpay Burak

AU - Prinslow, Eric A

AU - Voleti, Rashmi

AU - Haussinger, Daniel

AU - Bonvin, Alexandre M J J

AU - Tomchick, Diana R

AU - Vendruscolo, Michele

AU - Graham, Bimbil

AU - Sudhof, Thomas C

AU - Rizo, Josep

PY - 2015

Y1 - 2015

N2 - 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.

AB - 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.

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DO - 10.1038/nsmb.3035

M3 - Article

SN - 1545-9993

VL - 22

SP - 555

EP - 564

JO - Nature Structural & Molecular Biology

JF - Nature Structural & Molecular Biology

IS - 7

ER -

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

Abstract

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Tags and algorithms for studies of protein structures and interactions

Expanding the molecular tool set for structural studies of proteins and their complexes

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

Abstract

Access to Document

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Projects

Tags and algorithms for studies of protein structures and interactions

Expanding the molecular tool set for structural studies of proteins and their complexes

Cite this