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Mol Biol Cell. 2019 Jun 1;30(12):1390-1405. doi: 10.1091/mbc.E18-10-0649. Epub 2019 Apr 3.

The desmosome is a mesoscale lipid raft-like membrane domain.

Author information

1
Department of Cell Biology, Emory University School of Medicine, Atlanta, GA 30322.
2
Department of Graduate Program in Biochemistry, Cell and Developmental Biology, Emory University School of Medicine, Atlanta, GA 30322.
3
Department of Graduate Program in Cancer Biology, Emory University School of Medicine, Atlanta, GA 30322.
4
Buchmann Institute for Molecular Life Sciences, Goethe University Frankfurt, 60323 Frankfurt, Germany.
5
Institute for Biophysics, Goethe University Frankfurt, 60323 Frankfurt, Germany.
6
Department of Integrative Biology and Pharmacology, University of Texas Health Science Center at Houston, Houston, TX 77030.
7
Department of Oral Biology, College of Dentistry, University of Nebraska Medical Center, Lincoln, NE 68583.
8
Department of Cell, Developmental, and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL 35294.
9
Center for Supercentenarian Medical Research, Keio University School of Medicine, Tokyo 160-8582, Japan.
10
National Research Institute for Child Health and Development, Tokyo, Japan.
11
Department of Dermatology, Asahikawa Medical University, Asahikawa, Hokkaido 078-8510, Japan.
12
Department of Dermatology, Keio University School of Medicine, Tokyo 160-8582, Japan.
13
Department of Dermatology, Emory University School of Medicine, Atlanta, GA 30322.

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.

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