Cis glycan–glycan interactions organize membrane nanodomains that tune receptor signaling
The plasma membrane (PM) is generally viewed as organized by coordinated interactions among proteins and lipids, largely overlooking the cell’s most extensive surface chemistry, the glycan layer. Here, we directly detect specific cis glycan–glycan interactions using single-molecule imaging of 39 chemically synthesized fluorescent ganglioside analogs in living cells and defined lipid bilayers. All gangliosides examined form transient, metastable homodimers via homophilic glycan interactions, which are stabilized by cholesterol to generate nanoscale ganglioside homodimer rafts. They represent fundamental organizing units underlying PM nano-heterogeneity. Using EGF receptor (EGFR) as a representative receptor, we show that the interactions of paired GM3 glycans in the GM3 homodimer raft with defined N-linked glycans on EGFR suppress ligand-independent EGFR dimerization by reducing the dimer formation rate and enhancing dissociation, and continue to slow dimerization after EGF stimulation. Our findings establish cis glycan–glycan interactions as an organizing principle of PM organization and receptor regulation. Cell surfaces are coated with glycans, but how these sugars organize membranes and regulate receptors remains unclear. Here, authors show that direct glycan–glycan interactions form nanoscale ganglioside raft domains that restrain EGFR signaling
Authors
- Eriko Yamaguchi
- Masataka Nagaoka (ORCID: https://orcid.org/0000-0002-1735-7319)
- Takahiro Fujiwara (ORCID: https://orcid.org/0000-0001-5576-759X)
- Sachi Asano
- Yoshio Yamauchi (ORCID: https://orcid.org/0000-0001-5559-4596)
- Rahul Chadda (ORCID: https://orcid.org/0000-0001-6710-3985)
- Hiromune Ando (ORCID: https://orcid.org/0000-0002-0551-0830)
- Kenichi Suzuki (ORCID: https://orcid.org/0000-0002-8436-5757)
- Koichiro M. Hirosawa (ORCID: https://orcid.org/0000-0003-0170-3755)
- Naoko Komura (ORCID: https://orcid.org/0000-0002-8104-750X)
- Koichi Furukawa (ORCID: https://orcid.org/0000-0002-3321-9784)
- Kenichi Morigaki (ORCID: https://orcid.org/0000-0002-2454-6513)
- Akihiro Kusumi (ORCID: https://orcid.org/0000-0002-9558-6950)
- Yukichi Kitamura (ORCID: https://orcid.org/0000-0002-2704-2716)
- Akihiro Imamura (ORCID: https://orcid.org/0000-0002-7860-992X)
- Maina Takahashi
- Ayano Yamazaki
- Shusaku Shibutani
- Taka A. Tsunoyama
- Keiko Furukawa
Institutions
- Suzuki (Japan) (JP)
- Okinawa Institute of Science and Technology Graduate University (JP)
- Yamaguchi University (JP)
- Chubu University (JP)
- Kyoto University (JP)
- Gifu University (JP)
- Nagoya University (JP)
- Kobe University (JP)
Publication Details
- Journal
- Nature Communications
- Published
- 2026-08-27
- DOI
- https://doi.org/10.1038/s41467-026-76857-x
- Primary Topic
- Lipid Membrane Structure and Behavior
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Takeda Science Foundation
- University of Washington
- Uehara Memorial Foundation
- Mizutani Foundation for Glycoscience
- Japan Agency for Medical Research and Development
- Keio University
- Ministry of Education, Culture, Sports, Science and Technology
- Nakatani Foundation for Advancement of Measuring Technologies in Biomedical Engineering
- Japan Society for the Promotion of Science
- Japan Science and Technology Agency
- Canadian Glycomics Network
- Core Research for Evolutional Science and Technology