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.
journal_name
Mol Biol Celljournal_title
Molecular biology of the cellauthors
Lewis JD,Caldara AL,Zimmer SE,Stahley SN,Seybold A,Strong NL,Frangakis AS,Levental I,Wahl JK 3rd,Mattheyses AL,Sasaki T,Nakabayashi K,Hata K,Matsubara Y,Ishida-Yamamoto A,Amagai M,Kubo A,Kowalczyk APdoi
10.1091/mbc.E18-10-0649subject
Has Abstractpub_date
2019-06-01 00:00:00pages
1390-1405issue
12eissn
1059-1524issn
1939-4586journal_volume
30pub_type
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