Molecular mechanism of the flotillin complex in membrane microdomain organization

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Molecular mechanism of the flotillin complex in membrane microdomain organization

Authors

Lu, M.-A.; Qian, Y.; Ma, L.; Guo, Q.; Gao, N.

Abstract

Flotillin-1 and flotillin-2, initially identified as markers of lipid rafts, assemble together as hetero-oligomers and facilitate the organization of flotillin membrane microdomains, which play a crucial role in various cellular processes, such as endocytosis, protein sorting, and vesicle trafficking. However, the molecular mechanisms underlying flotillin oligomerization and flotillin microdomain organization remain incompletely understood. Here we present the cryo-electron microscopy structure of the human flotillin complex, at an overall resolution of 3.57 angstrom. It demonstrates that flotillin-1 and -2 are alternately arranged to form a 44-mer ring structure. This dome-shaped complex is hollow and sealed, attaching to the cytoplasmic leaflet of the plasma membrane and encompassing a circular domain with a diameter of approximately 30 nm. These structural features demonstrate a direct role for the flotillin complex in segregating the membrane to organize an isolated microdomain and also suggests a potential regulatory role in sequestering its interacting proteins. The cryo-electron tomography study further demonstrates the structural plasticity of the flotillin complexes in situ, indicative of dynamic conformational changes during their functional activities. In addition, aggregations of the flotillin complexes on the plasma membrane or intracellular vesicles, are frequently observed. Our data suggest that the flotillin complex constitutes the basic structural unit of membrane microdomains, and the further clustering of flotillin complexes might facilitate the formation of larger and more elaborate membrane microdomains. These findings enhance our understanding of the architecture of the SPFH family proteins and their common role in membrane microdomain organization, and more importantly, provide models for explaining the diverse functions of flotillin proteins in different biological processes.

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