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The nanomechanical mechanism of exocytotic fusion pore formation

Final Report Summary - THE FUSION MACHINE (The nanomechanical mechanism of exocytotic fusion pore formation)

Cells perform their functions in the body using sophisticated molecular machines. These machines are uniquely assembled protein complexes with a dimension of a few nanometers, which is a millionths of a millimeter. Elucidation of the structure and function of these machines is the basis for a mechanistic understanding of cellular functions from signal processing to muscle contraction.
In this project the molecular machine, which releases neurotransmitters and hormones in the body was investigated. Like a motorized door opener, this machine opens a door allowing release of transmitter molecules from tiny storage compartments inside the cell, the secretory vesicles, to the outside of the cell. For this project a new method was developed that made it possible to study for the first time changes in the structure of the door opener in direct relation to the opening of the gate. The method uses specially developed microfabricated devices, which can precisely determine the time and location of release of individual transmitter packets. At the same time advanced optical fluorescence microscopy, which images only changes on the cell surface is used to detect structural changes in one of the protein components of the molecular machine.
The detailed molecular movements that occur during opening of the gate were visualized and showed for the first time the details how the interactions of the molecules of this machine achieve their task. Tetanus toxin destroys essential components of this machine and the widely known BoTox treatment modifies this machine and thereby reduces transmitter release. The project revealed how the BoTox modification impairs the nanomechanical function of the complex. The precise understanding of the molecular mechanics may lead to new treatment strategies. It will also advance our understanding of the mechanisms by which viruses enter cells because they use closely related mechanisms.