Synaptotagmin activates membrane fusion through a Ca2+-dependent trans interaction with phospholipids

Alexander Stein, Anand Radhakrishnan, Dietmar Riedel, Dirk Fasshauer, Reinhard Jahn*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

135 Scopus citations


Synaptotagmin-1 is the calcium sensor for neuronal exocytosis, but the mechanism by which it triggers membrane fusion is not fully understood. Here we show that synaptotagmin accelerates SNARE-dependent fusion of liposomes by interacting with neuronal Q-SNARES in a Ca2+-independent manner. Ca2+-dependent binding of synaptotagmin to its own membrane impedes the activation. Preventing this cis interaction allows Ca2+ to trigger synaptotagmin binding in trans, accelerating fusion. However, when an activated SNARE acceptor complex is used, synaptotagmin has no effect on fusion kinetics, suggesting that synaptotagmin operates upstream of SNARE assembly in this system. Our results resolve major discrepancies concerning the effects of full-length synaptotagmin and its C2AB fragment on liposome fusion and shed new light on the interactions of synaptotagmin with SNAREs and membranes. However, our findings also show that the action of synaptotagmin on the fusion-arrested state of docked vesicles in vivo is not fully reproduced in vitro.

Original languageEnglish (US)
Pages (from-to)904-911
Number of pages8
JournalNature Structural and Molecular Biology
Issue number10
StatePublished - Oct 2007
Externally publishedYes

Bibliographical note

Funding Information:
We thank U. Ries for expert technical assistance, M. Holt for help with calcium measurements, S. Pabst for cloning, and P. Burkhardt and I. Bethani for valuable comments on the manuscript. Ca2+-binding mutants of the full-length protein were kind gifts from T. Südhof (Howard Hughes Medical Institute, University of Texas Southwestern). This work was supported by US National Institutes of Health grant P01 GM072694 (to R.J.) and the Boehringer Ingelheim Fonds (to A.S.).

ASJC Scopus subject areas

  • Molecular Biology
  • Structural Biology


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