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bioRxiv · 10.1101/2024.05.25.595881

Molecular mechanism of the flotillin complex in membrane microdomain organization

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

Flotillin-1 and flotillin-2 form hetero-oligomers to create flotillin membrane microdomains essential for endocytosis and protein sorting. However, the mechanisms of flotillin oligomerization and microdomain organization remain incompletely understood. Here, we present the cryo-EM structure of human flotillin complex, showing that flotillin-1 and -2 form a 44-mer, membrane attached, and dome-shaped structure that defines a 30-nm circular membrane domain. The cryo-ET data demonstrates that while attached to the cytoplasmic leaflet in situ, flotillin complexes possess intrinsic structural plasticity on the native membrane. Each flotillin complex may represent a fundamental unit of membrane microdomains, with their clustering enabling the formation of larger and more elaborate domains. We further reveal that phosphorylation at residues Y160 (flotillin-1) and Y163 (flotillin-2) may act as a molecular switch to modulate complex assembly, potentially regulating its function in endocytosis. These findings demonstrate the molecular mechanism of flotillin-mediated membrane segregation and microdomain formation, and suggest a previously unrecognized role of flotillin in sequestrating membrane proteins.

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Lu, M.-A., Qian, Y., Ma, L., Guo, Q., Gao, N.. 2024-05-25. Molecular mechanism of the flotillin complex in membrane microdomain organization. https://doi.org/10.1101/2024.05.25.595881

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