New insights into the molecular basis of desmoplakin- and desmin-related cardiomyopathies.
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.
Lapouge
Karine
K
Clinic of Dermatology, University Hospital, Geneva, Rue Micheli-du-Crest 14, 1211-Geneva 14, Switzerland.
Fontao
Lionel
L
Champliaud
Marie-France
MF
Jaunin
Fabienne
F
Frias
Miguel A
MA
Favre
Bertrand
B
Paulin
Denise
D
Green
Kathleen J
KJ
Borradori
Luca
L
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
D003893:Desmin; D051180:Desmoplakins; D050505:Mutant Proteins