Plakin Proteins, Hemidesmosomes and Human Disease

Abstract

The plakin proteins are a family of cytolinker proteins that connect elements of the cell cytoskeleton to each other and to junctional complexes at the cell membrane. There are seven mammalian plakin proteins and they are characterised by the presence of a plakin domain and/or a plakin repeat domain. The plakins play a vital role in maintaining the integrity of tissues, such as the skin and heart, which are subjected to mechanical stress. Two plakin proteins, plectin and bullous pemphigoid antigen 1 (BPAG1), are essential components of hemidesmosomes, cell–extracellular matrix junctions of epithelial cells, and inherited mutations in either can result in the skin blistering disease epidermolysis bullosa simplex. Mutations in the desmosomal plakin protein desmoplakin can cause the heart muscle disorder arrhythmogenic right ventricular dysplasia, a common cause of sudden cardiac arrest and death in young adults. Plakin proteins are targeted by pathogenic autoantibodies in the skin blistering diseases bullous pemphigoid and paraneoplastic pemphigus.

Key Concepts:

  • The plakin proteins are a family of cytolinker proteins that connect elements of the cell cytoskeleton to each other and to junctional complexes at the cell membrane.

  • Seven plakin proteins are found in mammals; plectin, BPAG1, desmoplakin, envoplakin, periplakin, microtubule–actin crosslinking factor 1 and epiplakin.

  • Plectin and BPAG1 are important constituents of hemidesmosomes, cell–extracellular matrix junctions.

  • Mutations in plakin proteins can result in skin blistering disease, muscular dystrophy, autonomic neuropathy and cardiomyopathy.

  • Plakin proteins have been implicated in the autoimmune skin blistering diseases bullous pemphigoid and paraneoplastic pemphigus.

Keywords: plakin; cytolinker; hemidesmosome; plectin; BPAG1; desmoplakin; envoplakin; periplakin; MACF1; epiplakin

Figure 1.

Structure of the plakin proteins. Alternative splicing results in number of N‐terminal plectin, bullous pemphigoid antigen 1 (BPAG1) and microtubule‐actin crosslinking factor 1 (MACF1) variants. These, and the rodless plectin isoform, are omitted for the sake of simplicity. Plakin domains of plakin proteins are comprised of a number of spectrin repeats and a Src homology‐3 (SH3) domain. Plectin, BPAG1a, BPAG1b and MACF1 each have nine spectrin repeats, BPAG1e has eight and desmoplakin, envoplakin and periplakin each have six. Note that the figure is not drawn to scale. Glycine‐serine‐arginine, GSR; gas2‐related, GAR.

Figure 2.

Schematic model of a hemidesmosome showing the location of the plakin proteins plectin and BPAG1e. Plectin and BPAG1e domains are shown in colour (as Figure ). Other principal protein components of hemidesmosomes (i.e. α6β4 integrin and BPAG2) are shown in greyscale; the tetraspanin CD151 is not shown. Hemidesmosomes link the intermediate filament (IF) cytoskeleton to the extracellular matrix protein laminin‐5 (laminin 332). During hemidesmosome assembly primary contact between plectin and β4 integrin is established by the actin‐binding domain of plectin, and localisation of BPAG1e into hemidesmosomes depends on its plakin domain. Many other interactions stabilise hemidesmosomes including those between the plakin domain of plectin and β4, plectin and BPAG2, and BPAG2 and β4. Plasma membrane, PM; basement membrane, BM.

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Further Reading

Garrod D and Chidgey M (2008) Desmosome structure, composition and function. Biochimica et Biophysica Acta 1778: 572–587.

Jefferson JJ, Leung CL and Liem RKH (2004) Plakins: goliaths that link cell junctions and the cytoskeleton. Nature Reviews Molecular Cell Biology 5: 542–553.

de Pereda JM, Ortega E, Alonso‐Garcia N, Gomez‐Hernandez M and Sonnenberg A (2009) Advances and perspectives of the architecture of hemidesmosomes. Lessons from structural biology. Cell Adhesion and Migration 3: 361–364.

Sonnenberg A and Liem RKH (2007) Plakins in development and disease. Experimental Cell Research 313: 2189–2203.

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Chidgey, Martyn(Oct 2012) Plakin Proteins, Hemidesmosomes and Human Disease. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0024527]