Mécanismes moléculaires régulant les machineries de fusion intracellulaires (SNAREs et Mitofusines) – REGULMAFUS
Membrane fusion is a fundamental biological process which is central to many areas of physiology, including neuronal communication, viral infection, and the maintenance of shape and function of mitochondria. The fusion of biological membranes uses complex molecular machineries, orchestrated by specialized proteins, and regulated by various factors (lipids or proteins) which facilitate fusion (for example, by inducing local membrane curvature), and/or ensure that fusion occurs at the right time and place (for example, by trapping and releasing the fusion machinery in response to particular signals). All intracellular membrane fusion events, except those involving mitochondria, are orchestrated by proteins from the SNARE family. Among them, SNARE proteins involved in neuronal communication constitute the best described intracellular fusion machinery, whose core molecular mechanisms and regulatory components are now widely used as paradigms for SNARE function and regulation. With this proposal, we want to extend our current biophysical understanding of SNARE fusion machineries by studying the core mechanisms and regulatory components of SNARE proteins involved in neuritogenesis. In addition, we propose to elucidate the function and regulation of the other, largely unknown, intracellular fusion machinery: that controlling mitochondrial dynamics. We will reconstitute fusion proteins or fragments of these proteins into various artificial lipidic platforms (e.g. small, large or giant liposomes), and use some biophysical assays (e.g. single liposome docking and fusion through confocal microscopy, adhesion/fusion of giant liposomes though micromanipulation) to gain insight into how these proteins execute their function. These experiments will be performed in the absence or the presence of various known in vivo regulators (lipids or proteins) with unknown molecular mechanisms.
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