title: Different roles of cadherins in the assembly and structural integrity of the desmosome complex.
abstract: Adhesion between cells is established by the formation of specialized intercellular junctional complexes, such as desmosomes. Desmosomes contain isoforms of two members of the cadherin superfamily of cell adhesion proteins, desmocollins (Dsc) and desmogleins (Dsg), but their combinatorial roles in desmosome assembly are not understood. To uncouple desmosome assembly from other cell-cell adhesion complexes, we used micro-patterned substrates of Dsc2aFc and/or Dsg2Fc and collagen IV; we show that Dsc2aFc, but not Dsg2Fc, was necessary and sufficient to recruit desmosome-specific desmoplakin into desmosome puncta and produce strong adhesive binding. Single-molecule force spectroscopy showed that monomeric Dsc2a, but not Dsg2, formed Ca(2+)-dependent homophilic bonds, and that Dsg2 formed Ca(2+)-independent heterophilic bonds with Dsc2a. A W2A mutation in Dsc2a inhibited Ca(2+)-dependent homophilic binding, similar to classical cadherins, and Dsc2aW2A, but not Dsg2W2A, was excluded from desmosomes in MDCK cells. These results indicate that Dsc2a, but not Dsg2, is required for desmosome assembly through homophilic Ca(2+)- and W2-dependent binding, and that Dsg2 might be involved later in regulating a switch to Ca(2+)-independent adhesion in mature desmosomes.
authors.affiliation: Cancer Biology Program, Stanford University, Stanford, CA 94305, USA.
authors.forename: Molly
authors.initials: M
authors.lastname: Lowndes
authors.affiliation: Department of Physics and Astronomy, Iowa State University, Ames, IA 50011, USA Ames Laboratory, United States Department of Energy, Ames, IA 50011, USA.
authors.forename: Sabyasachi
authors.initials: S
authors.lastname: Rakshit
authors.affiliation: Department of Physics and Astronomy, Iowa State University, Ames, IA 50011, USA Ames Laboratory, United States Department of Energy, Ames, IA 50011, USA.
authors.forename: Omer
authors.initials: O
authors.lastname: Shafraz
authors.affiliation: Institut Jacques Monod, Unité Mixte de Recherche 7592, Centre National de la Recherche Scientifique, and Université Paris-Diderot, 75013 Paris, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Borghi
authors.affiliation: Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Harmon
authors.affiliation: Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
authors.forename: Kathleen J
authors.initials: KJ
authors.lastname: Green
authors.affiliation: Department of Physics and Astronomy, Iowa State University, Ames, IA 50011, USA Ames Laboratory, United States Department of Energy, Ames, IA 50011, USA.
authors.forename: Sanjeevi
authors.initials: S
authors.lastname: Sivasankar
authors.affiliation: Cancer Biology Program, Stanford University, Stanford, CA 94305, USA Department of Biology, Stanford University, Stanford, CA 94305, USA Department of Molecular and Cellular Physiology, Stanford University, Stanford, CA 94305, USA wjnelson@stanford.edu.
authors.forename: W James
authors.initials: WJ
authors.lastname: Nelson
mesh_terms: D000818:Animals; D015820:Cadherins / Q000378:metabolism*; D002448:Cell Adhesion / Q000502:physiology; D015815:Cell Adhesion Molecules / Q000378:metabolism; D051182:Desmogleins / Q000378:metabolism; D003896:Desmosomes / Q000378:metabolism*; D004285:Dogs; D057809:HEK293 Cells; D006801:Humans; D061985:Madin Darby Canine Kidney Cells; D013057:Spectrum Analysis
chemical_list: D015820:Cadherins; D015815:Cell Adhesion Molecules; D051182:Desmogleins
keywords: Adhesion; Desmocollin; Desmoglein; Desmosome