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Vol. 19, Issue 8, 3379-3389, August 2008

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A Role for Soluble N-Ethylmaleimide-sensitive Factor Attachment Protein Receptor Complex Dimerization during Neurosecretion

Elena Fdez^*,, Thomas A. Jowitt^,, Ming-Chuan Wang, Manisha Rajebhosale, Keith Foster, Jordi Bella, Clair Baldock, Philip G. Woodman, and Sabine Hilfiker^*

*Institute of Parasitology and Biomedicine "López-Neyra," Consejo Superior de Investigaciones Cientificas, 18100 Granada, Spain; Faculty of Life Sciences, The University of Manchester, Manchester M13 9PT, United Kingdom; and Syntaxin Ltd., Abingdon, Oxon OX14 3YS, United Kingdom

Submitted January 9, 2008; Revised April 30, 2008; Accepted May 21, 2008
Monitoring Editor: Thomas F. J. Martin

The interactions underlying the cooperativity of soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complexes during neurotransmission are not known. Here, we provide a molecular characterization of a dimer formed between the cytoplasmic portions of neuronal SNARE complexes. Dimerization generates a two-winged structure in which the C termini of cytosolic SNARE complexes are in apposition, and it involves residues from the vesicle-associated SNARE synaptobrevin 2 that lie close to the cytosol–membrane interface within the full-length protein. Mutation of these residues reduces stability of dimers formed between SNARE complexes, without affecting the stability of each individual SNARE complex. These mutations also cause a corresponding decrease in the ability of botulinum toxin-resistant synaptobrevin 2 to rescue regulated exocytosis in toxin-treated neuroendocrine cells. Moreover, such synaptobrevin 2 mutants give rise to a dominant-negative inhibition of exocytosis. These data are consistent with an important role for SNARE complex dimers in neurosecretion.

These authors contributed equally to this work.

Address correspondence to: Sabine Hilfiker (sabine.hilfiker{at}ipb.csic.es)

Abbreviations used: MALLS, multiangle laser light scattering; SAXS, small angle X-ray scattering; SNARE, soluble N-ethylmaleimide-sensitive factor attachment protein receptor; syb2, synaptobrevin 2; TEM, transmission electron microscopy.

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