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Cited 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·2026·Nature Communications
DOI 10.1038/s41467-026-69197-3

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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, flotillin complexes possess intrinsic structural plasticity in situ 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. Flotillins are key organizers of membrane microdomains essential for cellular functions. Here, authors determine the structure of the human flotillin complex both in vitro and in situ, revealing its assembly into a dome-shaped oligomer that serves as a scaffold for membrane organization.

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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
Springer Science and Business Media LLC
Published
2026-02-09
Volume
17
Issue
1
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-026-69197-3
OpenAlex
W7128440024
Cited by
13
References
2
Citations by year
2026: 8
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)
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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