title: The head domain of plakophilin-1 binds to desmoplakin and enhances its recruitment to desmosomes. Implications for cutaneous disease.
abstract: The contribution of desmosomes to epidermal integrity is evident in the inherited blistering disorder associated with the absence of a functional gene for plakophilin-1. To define the function of plakophilin-1 in desmosome assembly, interactions among the desmosomal cadherins, desmoplakin, and the armadillo family members plakoglobin and plakophilin-1 were examined. In transient expression assays, plakophilin-1 formed complexes with a desmoplakin amino-terminal domain and enhanced its recruitment to cell-cell borders; this recruitment was not dependent on the equimolar expression of desmosomal cadherins. In contrast to desmoplakin-plakoglobin interactions, the interaction between desmoplakin and plakophilin-1 was not mediated by the armadillo repeat domain of plakophilin-1 but by the non-armadillo head domain, as assessed by yeast two-hybrid and recruitment assays. We propose a model whereby plakoglobin serves as a linker between the cadherins and desmoplakin, whereas plakophilin-1 enhances lateral interactions between desmoplakin molecules. This model suggests that epidermal lesions in patients lacking plakophilin-1 are a consequence of the loss of integrity resulting from a decrease in binding sites for desmoplakin and intermediate filaments at desmosomes.
authors.affiliation: Department of Dermatology and the Robert H. Lurie Cancer Center, Northwestern University Medical School, Chicago, Illinois 60611, USA.
authors.forename: A P
authors.initials: AP
authors.lastname: Kowalczyk
authors.forename: M
authors.initials: M
authors.lastname: Hatzfeld
authors.forename: E A
authors.initials: EA
authors.lastname: Bornslaeger
authors.forename: D S
authors.initials: DS
authors.lastname: Kopp
authors.forename: J E
authors.initials: JE
authors.lastname: Borgwardt
authors.forename: C M
authors.initials: CM
authors.lastname: Corcoran
authors.forename: A
authors.initials: A
authors.lastname: Settler
authors.forename: K J
authors.initials: KJ
authors.lastname: Green
mesh_terms: D000818:Animals; D019556:COS Cells; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D051180:Desmoplakins; D003896:Desmosomes / Q000378:metabolism*; D051191:Plakophilins; D011485:Protein Binding; D011487:Protein Conformation; D011506:Proteins / Q000378:metabolism*; D011817:Rabbits; D012871:Skin Diseases / Q000503:physiopathology*; D051185:gamma Catenin
chemical_list: D015815:Cell Adhesion Molecules; D003598:Cytoskeletal Proteins; D051180:Desmoplakins; D051191:Plakophilins; D011506:Proteins; D051185:gamma Catenin