title: New insights into the molecular basis of desmoplakin- and desmin-related cardiomyopathies.
abstract: Desmosomes are intercellular adhesive complexes that anchor the intermediate filament cytoskeleton to the cell membrane in epithelia and cardiac muscle cells. The desmosomal component desmoplakin plays a key role in tethering various intermediate filament networks through its C-terminal plakin repeat domain. To gain better insight into the cytoskeletal organization of cardiomyocytes, we investigated the association of desmoplakin with desmin by cell transfection, yeast two-hybrid, and/or in vitro binding assays. The results indicate that the association of desmoplakin with desmin depends on sequences within the linker region and C-terminal extremity of desmoplakin, where the B and C subdomains contribute to efficient binding; a potentially phosphorylatable serine residue in the C-terminal extremity of desmoplakin affects its association with desmin; the interaction of desmoplakin with non-filamentous desmin requires sequences contained within the desmin C-terminal rod portion and tail domain in yeast, whereas in in vitro binding studies the desmin tail is dispensable for association; and mutations in either the C-terminus of desmoplakin or the desmin tail linked to inherited cardiomyopathy seem to impair desmoplakindesmin interaction. These studies increase our understanding of desmoplakin-intermediate filament interactions, which are important for maintenance of cytoarchitecture in cardiomyocytes, and give new insights into the molecular basis of desmoplakin- and desmin-related human diseases.
authors.affiliation: Clinic of Dermatology, University Hospital, Geneva, Rue Micheli-du-Crest 14, 1211-Geneva 14, Switzerland.
authors.forename: Karine
authors.initials: K
authors.lastname: Lapouge
authors.forename: Lionel
authors.initials: L
authors.lastname: Fontao
authors.forename: Marie-France
authors.initials: MF
authors.lastname: Champliaud
authors.forename: Fabienne
authors.initials: F
authors.lastname: Jaunin
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Frias
authors.forename: Bertrand
authors.initials: B
authors.lastname: Favre
authors.forename: Denise
authors.initials: D
authors.lastname: Paulin
authors.forename: Kathleen J
authors.initials: KJ
authors.lastname: Green
authors.forename: Luca
authors.initials: L
authors.lastname: Borradori
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D009202:Cardiomyopathies / Q000235:genetics*; D002478:Cells, Cultured; D003893:Desmin / Q000235:genetics* / Q000378:metabolism; D051180:Desmoplakins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D050505:Mutant Proteins / Q000378:metabolism; D009154:Mutation; D032383:Myocytes, Cardiac / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D051381:Rats; D017208:Rats, Wistar; D020539:Sequence Analysis, Protein; D014018:Tissue Distribution; D014162:Transfection; D020798:Two-Hybrid System Techniques
chemical_list: D003893:Desmin; D051180:Desmoplakins; D050505:Mutant Proteins