25.5:
Cytoskeletal Linker Proteins – Plakins
Plakins are a family of large multidomain proteins that crosslink the different types of cytoskeletal filaments and connect them to the cell junctions on the plasma membrane.
Plakins are usually dimeric, where each protein domain has a distinct role. The characteristic plakin domain, which directs the attachment to the target region, is followed by a coiled-coil rod domain that helps in dimerization or oligomerization.
These domains associate with plakin repeats, linker subdomains, and glycine-serine-arginine domains in different combinations to construct distinct proteins with varied functions.
For example, desmoplakins found in desmosomes contain plakin repeats followed by a glycine-serine-arginine domain.
Plectin, another versatile cytoskeletal linker, comprises distinct and overlapping domains for binding each of the three types of cytoskeletal filaments, and membrane proteins like integrins.
25.5:
Cytoskeletal Linker Proteins – Plakins
Plakins are large proteins with binding domains for microtubules, microfilaments, intermediate filaments, and membrane-associated protein complexes at cell junctions. Plakin functions are evolutionarily conserved and are primarily involved in organizing the different components of the cytoskeleton by crosslinking them to each other and connecting them to the cell-matrix and cell adhesion complexes. They are also known to interact with signal transducers, serve as scaffolds for signaling complexes and modulate vesicle trafficking.
Plakins were initially found associated with intermediate filaments in desmosomes and hemidesmosomes, which are cell junctions in the epithelial tissues. Therefore, their function was believed to be restricted to maintaining epithelial tissue integrity. However, recent research has resulted in the discovery of new plakins with unique isoforms that arise through the alternative splicing of the plakin gene locus. These isoforms show tissue-specific expression profiles and have unique domain organizations and functions. These isoforms can also associate with the other cytoskeletal filaments and are functional in non-epithelial cells. For example, research on mice and invertebrates has demonstrated the role of plakins in non-epidermal cells such as neurons.
Disorders associated with Plakins
Plakins are cytolinkers crucial to cellular development and maintenance of tissue integrity. Therefore, any defect in the gene coding for plakin can result in various diseases that affect the skin, neuronal tissue, and cardiac and skeletal muscle. Mammals have seven proteins belonging to the plakins, such as desmoplakin, envoplakin, epiplakin, bullous pemphigoid antigen 1, microtubule‐actin crosslinking factor 1, periplakin, and plectin. In humans, mutations in any of these plakin genes result in disorders of the skin and muscular system. For example, mutations in genes coding for plectin result in a disease called epidermolysis bullosa simplex with muscular dystrophy, which results in fragile skin easily prone to blistering and damage and weakening of muscles over time.
Suggested Reading
- Bouameur, J. E., Favre, B., & Borradori, L. (2014). Plakins, a versatile family of cytolinkers, have roles in skin integrity and human diseases. Journal of Investigative Dermatology, 134(4), 885-894.
- Leung, C. L., Green, K. J., & Liem, R. K. (2002). Plakins: a family of versatile cytolinker proteins. Trends in cell biology, 12(1), 37-45.
- Jefferson, J. J., Leung, C. L., & Liem, R. K. (2004). Plakins: goliaths that link cell junctions and the cytoskeleton. Nature Reviews Molecular Cell Biology, 5(7), 542-553.