New insights into the molecular basis of desmoplakinand 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.

Phosphorylation of serine 4642 in the COOH-extremity of plectin by MNK2 and PKA modulates its interaction with intermediate filaments

“…We have previously shown that mutation of S2849 in desmoplakin has a positive impact on its association with IF proteins (Stappenbeck et al, 1994;Fontao et al, 2003;Lapouge et al, 2006), inhibits its cellular trafficking (Godsel et al, 2005) and promotes desmosome adhesive strength (Hobbs and Green, 2012). Our present findings reveal that phosphorylation of plectin S4642 also inhibits the association of plectin with various types of IFs, including epidermal K5/K14, simple K8/K18 keratins, type III IF proteins and type IV neurofilaments.…”

Cytokines as genetic modifiers in K5���/���mice and in human epidermolysis bullosa simplex

“…Although keratin genes are closely related and the keratin proteins are quite conserved, specific interaction partners for individual keratins have been identified. b4 Integrin and desmoplakin specifically interact with the type II keratin K5 and not with the type I keratin K14, linking keratin IFs to hemidesmosomes and desmosomes, respectively [Lapouge et al, 2006;Litjens et al, 2006]. Furthermore, K17, another type I keratin, was shown to interact with the scaffold-protein 14-3-3, an interaction so far not reported for K5 [Kim et al, 2006].…”

The Novel Desmin Mutant p.A120D Impairs Filament Formation, Prevents Intercalated Disk Localization, and Causes Sudden Cardiac Death

“…It is known that desmin is linked to the cardiac desmosome via the plaque protein desmoplakin. 46 Based on yeast 2 hybrid analyses, this protein interaction was claimed to be affected by the desmin mutant p.I451M. 46 However, the transgenic murine model of Mavroidis et al 47 revealed in contrast that this mutation affects the positioning of desmin to the z-bands but not in the ID.…”

“…46 Based on yeast 2 hybrid analyses, this protein interaction was claimed to be affected by the desmin mutant p.I451M. 46 However, the transgenic murine model of Mavroidis et al 47 revealed in contrast that this mutation affects the positioning of desmin to the z-bands but not in the ID. Thus, it remains an open question whether a specific (sub-)domain of desmin is linked to the ID via desmoplakin.…”