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Science 323 (5913): 512-516

Copyright © 2009 by the American Association for the Advancement of Science

Alternative Zippering as an On-Off Switch for SNARE-Mediated Fusion

Claudio G. Giraudo,1*{dagger} Alejandro Garcia-Diaz,1{dagger} William S. Eng,1,2 Yuhang Chen,2 Wayne A. Hendrickson,2 Thomas J. Melia,1{dagger} James E. Rothman1*{dagger}

Abstract: Membrane fusion between vesicles and target membranes involves the zippering of a four-helix bundle generated by constituent helices derived from target– and vesicle–soluble N-ethylmaleimide–sensitive factor attachment protein receptors (SNAREs). In neurons, the protein complexin clamps otherwise spontaneous fusion by SNARE proteins, allowing neurotransmitters and other mediators to be secreted when and where they are needed as this clamp is released. The membrane-proximal accessory helix of complexin is necessary for clamping, but its mechanism of action is unknown. Here, we present experiments using a reconstituted fusion system that suggest a simple model in which the complexin accessory helix forms an alternative four-helix bundle with the target-SNARE near the membrane, preventing the vesicle-SNARE from completing its zippering.

1 Department of Physiology and Cellular Biophysics, Columbia University, College of Physicians and Surgeons, 1150 Saint Nicholas Avenue, Russ Berrie Building, Room 520, New York, NY 10032, USA.
2 Department of Biochemistry and Molecular Biophysics, Columbia University, and Howard Hughes Medical Institute, New York, NY 10032, USA.

{dagger} Present address: Department of Cell Biology, School of Medicine, Yale University, 333 Cedar Street, New Haven, CT 06520, USA.

* To whom correspondence should be addressed. E-mail: james.rothman{at}yale.edu (J.E.R.); claudio.giraudo{at}yale.edu (C.G.G.)

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