Cells control the adhesion protein desmoplakin by modifying the tail end of the protein, and this process goes awry¹ in some patients with arrhythmogenic cardiomyopathy, according to a study in The Journal of Cell Biology. Desmoplakin is a key component² of the adhesive³ junctions⁴, known as desmosomes, that link cells together in tissues that undergo severe strain, such as the heart and skin. Its role is to anchor parts of the cytoskeleton to sites of cell-to-cell contact. Kathleen Green and colleagues at Northwestern University Feinberg School of Medicine determined⁵ how modifying desmoplakin's intracellular tail with phosphate and methyl groups affects the protein's interaction with the cytoskeleton.

 

The enzyme⁶ GSK3 added phosphate groups to desmoplakin's tail, and its loss spurred the protein to shift from desmosomes to the intermediate filaments⁷. Blocking GSK3 slowed desmoplakin's relocation from the intermediate filaments to the cells' boundaries during desmosome formation.

 

Methylation of four arginine residues⁸ in desmoplakin's tail had similar effects as phosphorylation. The team also found that methylation of one particular arginine, R2834, which is mutated in some patients with arrhythmogenic cardiomyopathy, was necessary for the phosphorylation of most tail serine residues because this modification⁹ drew GSK3 to desmoplakin. Mutating this arginine delayed desmoplakin's assembly into desmosomes, weakening intercellular connections so that cell layers broke apart under mechanical stress.

 

The results show that phosphorylation and methylation make desmoplakin more dynamic. Cells might be able to fine-tune desmoplakin's characteristics by adding and removing phosphates and methyl groups, and defects in this regulatory process might contribute to skin and heart diseases.

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