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Vol. 16, Issue 12, 5675-5685, December 2005
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* Department of Membrane Biophysics, Max-Planck-Institute for Biophysical Chemistry, 37077 Göttingen, Germany;
Department of Neurobiology, Max-Planck-Institute for Biophysical Chemistry, 37077 Göttingen, Germany;
Departments of Theoretical and Computational Biophysics, Max-Planck-Institute for Biophysical Chemistry, 37077 Göttingen, Germany; and
|| Department of Neurosciences, University of New Mexico Health Science Center, Albuquerque, NM 87131
Submitted July 5, 2005;
Revised September 6, 2005;
Accepted September 20, 2005
Monitoring Editor: Vivek Malhotra
The essential membrane fusion apparatus in mammalian cells, the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex, consists of four 
-helices formed by three proteins: SNAP-25, syntaxin 1, and synaptobrevin 2. SNAP-25 contributes two helices to the complex and is targeted to the plasma membrane by palmitoylation of four cysteines in the linker region. It is alternatively spliced into two forms, SNAP-25a and SNAP-25b, differing by nine amino acids substitutions. When expressed in chromaffin cells from SNAP-25 null mice, the isoforms support different levels of secretion. Here, we investigated the basis of that different secretory phenotype. We found that two nonconservative substitutions in the N-terminal SNARE domain and not the different localization of one palmitoylated cysteine cause the functional difference between the isoforms. Biochemical and molecular dynamic simulation experiments revealed that the two substitutions do not regulate secretion by affecting the property of SNARE complex itself, but rather make the SNAP-25b-containing SNARE complex more available for the interaction with accessory factor(s).
Abbreviations used: SNARE, soluble N-ethylmaleimide-sensitive factor attachment protein receptor; SNAP-25, synaptosome-associated protein of 25 kDa.
These authors contributed equally to this work.
Address correspondence to: Jakob B. Sørensen (jsoeren{at}gwdg.de).
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