期刊
NATURE STRUCTURAL & MOLECULAR BIOLOGY
卷 22, 期 7, 页码 555-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nsmb.3035
关键词
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资金
- US National Institutes of Health [S10RR026461, K99NS087086, NS040944]
- Welch Foundation [I-1304]
- Australian Research Council (ARC) [DP150100383]
- ARC [FT130100838]
- Swiss National Science Foundation [200021_130263]
- Swiss National Science Foundation (SNF) [200021_130263] Funding Source: Swiss National Science Foundation (SNF)
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 beta-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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