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

Research output: Contribution to journalArticleResearchpeer-review

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 and Molecular Biology
Volume22
Issue number7
DOIs
Publication statusPublished - 2015

Cite this

Brewer, K. D., Bacaj, T., Cavalli, A., Camilloni, C., Swarbrick, J. D., Liu, J., ... Rizo, J. (2015). Dynamic binding mode of a Synaptotagmin-1-SNARE complex in solution. Nature Structural and Molecular Biology, 22(7), 555 - 564. https://doi.org/10.1038/nsmb.3035
Brewer, Kyle Daniel ; Bacaj, Taulant ; Cavalli, Andrea ; Camilloni, Carlo ; Swarbrick, James David ; Liu, Jin ; Zhou, Amy ; Zhou, Peng ; Barlow, Nicholas ; Xu, Junjie ; Seven, Alpay Burak ; Prinslow, Eric A ; Voleti, Rashmi ; Haussinger, Daniel ; Bonvin, Alexandre M J J ; Tomchick, Diana R ; Vendruscolo, Michele ; Graham, Bimbil ; Sudhof, Thomas C ; Rizo, Josep. / Dynamic binding mode of a Synaptotagmin-1-SNARE complex in solution. In: Nature Structural and Molecular Biology. 2015 ; Vol. 22, No. 7. pp. 555 - 564.
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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",
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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 and Molecular Biology, vol. 22, no. 7, pp. 555 - 564. https://doi.org/10.1038/nsmb.3035

Dynamic binding mode of a Synaptotagmin-1-SNARE complex in solution. / Brewer, Kyle Daniel; Bacaj, Taulant; Cavalli, Andrea; Camilloni, Carlo; Swarbrick, James David; Liu, Jin; Zhou, Amy; Zhou, Peng; Barlow, Nicholas; Xu, Junjie; Seven, Alpay Burak; Prinslow, Eric A; Voleti, Rashmi; Haussinger, Daniel; Bonvin, Alexandre M J J; Tomchick, Diana R; Vendruscolo, Michele; Graham, Bimbil; Sudhof, Thomas C; Rizo, Josep.

In: Nature Structural and Molecular Biology, Vol. 22, No. 7, 2015, p. 555 - 564.

Research output: Contribution to journalArticleResearchpeer-review

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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U2 - 10.1038/nsmb.3035

DO - 10.1038/nsmb.3035

M3 - Article

VL - 22

SP - 555

EP - 564

JO - Nature Structural Biology

JF - Nature Structural Biology

SN - 1545-9993

IS - 7

ER -

Brewer KD, Bacaj T, Cavalli A, Camilloni C, Swarbrick JD, Liu J et al. Dynamic binding mode of a Synaptotagmin-1-SNARE complex in solution. Nature Structural and Molecular Biology. 2015;22(7):555 - 564. https://doi.org/10.1038/nsmb.3035