QBI Seminar: The nanomechanical mechanism of exocytotic fusion pore formation
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- Professor Manfred Lindau
Professor of Applied and Engineering Physics, Cornell University, Ithaca N.Y., USA
Title: The nanomechanical mechanism of exocytotic fusion pore formation
Abstract:
Vesicle fusion is a key process in cell biology. Fusion of vesicles with the plasma membrane mediates release of neurotransmitters, hormones, and many other compounds in response to specific stimuli by exocytosis. This release occurs from the interior of the secretory vesicle to the outside of the cell via formation of a fusion pore. The SNARE (Soluble NSF Attachment REceptor) complex, which in mammalian neurons and neuroendocrine cells is composed of the proteins synaptobrevin-2 (Syb2), syntaxin-1 (Syx1), and SNAP-25, plays a key role in vesicle fusion. One example for the medical relevance of SNARE complex function is the BoTox treatment, which inhibits transmitter release by specific cleavage of the SNARE protein SNAP-25. The remarkable significance of the discovery of the key components of vesicle fusion and their regulation has also been recognized in the 2013 year’s Nobel Prize for Medicine. Although the components are known, there is still no clear mechanistic model for fusion pore formation and fusion pore dilation.
The central project in my laboratory is the investigation of the precise nanomechanical mechanism by which the SNARE protein complex opens a fusion pore allowing release of transmitter molecules from secretory vesicles to the outside of the cell. In one approach we investigate specific mutations with respect to their impact on fusion rates and fusion pore properties. In a second approach we probe conformational changes in a protein complex utilizing Fluorescence Resonance Energy Transfer (FRET) and relate such changes in space and time to the opening of individual fusion pores. In a third approach we determine activation energies of conformational changes in the SNARE complex and the impact of specific mutations on by molecular dynamics simulations. The simulation results are compared to the impact of the same mutations on the function of the SNARE complex in vesicle fusion.
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