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.
Dynamic binding mode of a Synaptotagmin-1-SNARE complex in solution / K.D. Brewer, T. Bacaj, A. Cavalli, C. Camilloni, J.D. Swarbrick, J. Liu, A. Zhou, P. Zhou, N. Barlow, J. Xu, A.B. Seven, E.A. Prinslow, R. Voleti, D. Häussinger, A.M.J.J. Bonvin, D.R. Tomchick, M. Vendruscolo, B. Graham, T.C. Südhof, J. Rizo. - In: NATURE STRUCTURAL & MOLECULAR BIOLOGY. - ISSN 1545-9993. - 22:7(2015), pp. 555-564. [10.1038/nsmb.3035]
Dynamic binding mode of a Synaptotagmin-1-SNARE complex in solution
C. Camilloni;
2015
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.File | Dimensione | Formato | |
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