TY - JOUR
T1 - The desmosome is a mesoscale lipid raft–like membrane domain
AU - Lewis, Joshua D.
AU - Caldara, Amber L.
AU - Zimmer, Stephanie E.
AU - Stahley, Sara N.
AU - Seybold, Anna
AU - Strong, Nicole L.
AU - Frangakis, Achilleas S.
AU - Levental, Ilya
AU - Wahl, James K.
AU - Mattheyses, Alexa L.
AU - Sasaki, Takashi
AU - Nakabayashi, Kazuhiko
AU - Hata, Kenichiro
AU - Matsubara, Yoichi
AU - Ishida-Yamamoto, Akemi
AU - Amagai, Masayuki
AU - Kubo, Akiharu
AU - Kowalczyk, Andrew P.
N1 - Funding Information:
We thank Kathleen Green and members of the Kowalczyk lab for comments and insights during the preparation of this article. We also thank Joseph Lorent for help generating the TMD models. This work was supported by grants (R01AR048266, R01AR048266-13S1, and R01AR050501 to A.P.K.; LOEWE Dynamem to A.S.F.) and fellowships (F31AR066476 and T32GM008367 to J.D.L.) from the National Institutes of Health (NIH) and by the Practical Research Project for Rare/Intractable Diseases (16ek0109067h0003 to Y.M. and 16ek0109151h0002 to A.K.) from the Japan Agency for Medical Research and Development. I.L. is funded by the NIH/National Institute of General Medical Sciences (GM114282, GM124072, GM120351), the Volkswagen Foundation (grant 93091), and the Human Frontiers Science Program (RGP0059/2019). Additional support was provided by core facilities at Emory University, including the Integrated Cellular Imaging Core, the Emory Flow Cytometry Core, and the Cloning Division within Emory Integrated Genomics Core.
Publisher Copyright:
© 2019 Lewis, Caldara, et al.
PY - 2019
Y1 - 2019
N2 - 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.
AB - 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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U2 - 10.1091/mbc.E18-10-0649
DO - 10.1091/mbc.E18-10-0649
M3 - Article
C2 - 30943110
AN - SCOPUS:85067268511
SN - 1059-1524
VL - 30
SP - 1390
EP - 1405
JO - Molecular biology of the cell
JF - Molecular biology of the cell
IS - 12
ER -