The desmosome is a mesoscale lipid raft–like membrane domain

Joshua D. Lewis, Amber L. Caldara, Stephanie E. Zimmer, Sara N. Stahley, Anna Seybold, Nicole L. Strong, Achilleas S. Frangakis, Ilya Levental, James K. Wahl, Alexa L. Mattheyses, Takashi Sasaki, Kazuhiko Nakabayashi, Kenichiro Hata, Yoichi Matsubara, Akemi Ishida-Yamamoto, Masayuki Amagai, Akiharu Kubo, Andrew P. Kowalczyk

Research output: Contribution to journalArticle

6 Scopus citations

Abstract

Desmogleins (Dsgs) are cadherin family adhesion molecules essential for epidermal integrity. Previous studies have shown that desmogleins associate with lipid rafts, but the significance of this association was not clear. Here, we report that the desmoglein transmembrane domain (TMD) is the primary determinant of raft association. Further, we identify a novel mutation in the DSG1 TMD (G562R) that causes severe dermatitis, multiple allergies, and metabolic wasting syndrome. Molecular modeling predicts that this G-to-R mutation shortens the DSG1 TMD, and experiments directly demonstrate that this mutation compromises both lipid raft association and desmosome incorporation. Finally, cryo-electron tomography indicates that the lipid bilayer within the desmosome is ∼10% thicker than adjacent regions of the plasma membrane. These findings suggest that differences in bilayer thickness influence the organization of adhesion molecules within the epithelial plasma membrane, with cadherin TMDs recruited to the desmosome via the establishment of a specialized mesoscale lipid raft–like membrane domain.

Original languageEnglish (US)
Pages (from-to)1390-1405
Number of pages16
JournalMolecular biology of the cell
Volume30
Issue number12
DOIs
StatePublished - 2019

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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    Lewis, J. D., Caldara, A. L., Zimmer, S. E., Stahley, S. N., Seybold, A., Strong, N. L., Frangakis, A. S., Levental, I., Wahl, J. K., Mattheyses, A. L., Sasaki, T., Nakabayashi, K., Hata, K., Matsubara, Y., Ishida-Yamamoto, A., Amagai, M., Kubo, A., & Kowalczyk, A. P. (2019). The desmosome is a mesoscale lipid raft–like membrane domain. Molecular biology of the cell, 30(12), 1390-1405. https://doi.org/10.1091/mbc.E18-10-0649