The desmosome is a mesoscale lipid raft-like membrane domain

• Type of Material: Article
• Authors: Joshua D. Lewis, Emory University; Amber L. Caldara, Emory University; Stephanie E. Zimmer, Emory University; Sara N. Stahley, Emory University; Anna Seybold, Goethe University Frankfurt; Nicole L. Strong, Emory University; Achilleas S. Frangakis, Goethe University Frankfurt; Ilya Levental, University of Texas Health Science Center; James K. Wahl, University of Nebraska Medical Center; Alexa L. Mattheyses, University of Alabama Birmingham; Takashi Sasaki, Keio University; Kazuhiko Nakabayashi, National Research Institute for Child Health and Development; Kenichiro Hata, National Research Institute for Child Health and Development; Yoichi Matsubara, National Research Institute for Child Health and Development; Akemi Ishida-Yamamoto, Asahikawa Medical University; Masayuki Amagai, Keio University; Akiharu Kubo, Keio University; Andrew Kowalczyk, Emory University
• Language: English
• Date: 2019-06-01
• Publisher: American Society for Cell Biology
• Publication Version: Final Published Version
• Copyright Statement: © 2019 Lewis, Caldara, et al.
• License: Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported
• Final Published Version (URL): http://dx.doi.org/10.1091/mbc.E18-10-0649
• Title of Journal or Parent Work: Molecular Biology of the Cell
• ISSN: 1059-1524
• Volume: 30
• Issue: 12
• Start Page: 1390
• End Page: 1405
• Grant/Funding Information: 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).; 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.; 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.
• Keywords: PALMITOYLATION; PALMOPLANTAR KERATODERMA; DESMOGLEIN; CHOLESTEROL; PEMPHIGUS; Science & Technology; MULTIPLE ALLERGIES; DYNAMICS; MUTATIONS; SEVERE DERMATITIS; Cell Biology; Life Sciences & Biomedicine; BILAYER THICKNESS
• Research Categories: Biology, Cell; Health Sciences, Medicine and Surgery

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.