TCB Publications - Abstract

Andrew E. Blanchard, Mark J. Arcario, Klaus Schulten, and Emad Tajkhorshid. A highly tilted membrane configuration for the pre-fusion state of synaptobrevin. Biophysical Journal, 107:2112-2121, 2014. (PMC: PMC4223215)

BLAN2014 The SNARE complex plays a vital role in vesicle fusion arising during neuronal exocytosis. Key components in the regulation of SNARE complex formation, and ultimately fusion, are the transmembrane (TM) and linker regions of the vesicle associated protein, synaptobrevin. However, the membrane embedded structure of synaptobrevin in its pre- fusion state, which determines its interaction with other SNARE proteins during fusion, is largely unknown. This study reports all-atom molecular dynamics simulations of the pre- fusion configuration of synaptobrevin in a lipid bilayer, aimed at characterizing the insertion depth and the orientation of the protein in the membrane, as well as the nature of the amino acids involved in determining these properties. By characterizing the structural properties of both wild type and mutant synaptobrevin, the effects of C-terminal additions on tilt and insertion depth of membrane embedded synaptobrevin are determined. The simulations suggest a robust, highly tilted state for membrane embedded synaptobrevin with a helical connection between the TM and linker regions, leading to a new characterization of structural elements in pre-fusion synaptobrevin and providing a framework for interpreting past mutation experiments.

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