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PreprintCited by 13Cellular transport and secretionLipid Membrane Structure and BehaviorCaveolin-1 and cellular processes

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Molecular mechanisms of flotillin complexes in organizing membrane microdomains

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Lu, Ming-Ao, Qian, Yunwen, Ma, Liangwen, Hong, Jinzhi, Li, Xiaopeng, Yu, Li, Guo, Qiang, Gao, Ning·2024·Nature Communications
DOI 10.1101/2024.05.25.595881

Preprint — published as 10.1038/s41467-026-69197-3 · Paper page

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Abstract

Summary: 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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Metadata

Authors
Lu, M.-A., Qian, Y., Ma, L., Hong, J., Li, X., Yu, L., Guo, Q., & Gao, N.
Affiliations
Peking University (CN)
Corresponding author
  • Guo, Qiang
  • Gao, Ning
ORCID
Venue
Nature Communications
Publisher
openRxiv
Published
2024-05-25
Volume
17
Issue
1
ISSN
2041-1723 (ISSN-L)
DOI
10.1101/2024.05.25.595881
OpenAlex
W7128440024
Cited by
13
References
1
Citations by year
2026: 8 · 2025: 3 · 2024: 2
FWCI
27.17
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by-nc-nd)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Natural Science Foundation of China (92354306)
  • Beijing Natural Science Foundation (JQ24031)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Lipid Membrane Structure and Behavior
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Caveolin-1 and cellular processes
Keywords
flotillin-1, flotillin-2, lipid rafts, oligomerization, cryo-EM structure, cryo-electron tomography, phosphorylation, endocytosis, protein sorting, structural plasticity
MeSH terms
Endocytosis, Humans, Membrane Proteins, Phosphorylation, Cryoelectron Microscopy, Membrane Microdomains

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