Plakin Proteins, Hemidesmosomes and Human Disease

Martyn Chidgey, University of Birmingham, Birmingham, UK

Published online: October 2012

DOI: 10.1002/9780470015902.a0024527

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 (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; , BM.
close

References

Al‐Jassar C, Knowles T, Jeeves M et al. (2011) The nonlinear structure of the desmoplakin plakin domain and the effects of cardiomyopathy‐linked mutations. Journal of Molecular Biology 411: 1049–1061.

Angst BD, Nilles LA and Green KJ (1990) Desmoplakin II expression is not restricted to stratified epithelia. Journal of Cell Science 97: 247–257.

Anhalt GJ, Kim SC, Stanley JR et al. (1990) Paraneoplastic pemphigus. An autoimmune mucocutaneous disease associated with neoplasia. New England Journal of Medicine 323: 1729–1735.

Armstrong DK, McKenna KE, Purkis PE et al. (1999) Haploinsufficiency of desmoplakin causes a striate subtype of palmoplantar keratoderma. Human Molecular Genetics 8: 143–148.

Awad MM, Calkins H and Judge DP (2008) Mechanisms of disease: molecular genetics of arrhythmogenic right ventricular dysplasia/cardiomyopathy. Nature Clinical Practice Cardiovascular Medicine 5: 258–267.

Boczonadi V, McInroy L and Maatta A (2007) Cytolinker cross‐talk: periplakin N‐terminus interacts with plectin to regulate keratin organisation and epithelial migration. Experimental Cell Research 313: 3579–3591.

Boyer JG, Bernstein MA and Boudreau‐Lariviere C (2010) Plakins in striated muscle. Muscle and Nerve 41: 299–308.

Candi E, Schmidt R and Melino G (2005) The cornified envelope: a model of cell death in the skin. Nature Reviews Molecular Cell Biology 6: 328–340.

Choi H‐J, Park‐Snyder S, Pascoe LT, Green KJ and Weis WI (2002) Structures of two intermediate filament‐binding fragments of desmoplakin reveal a unique repeat motif structure. Nature Structural Biology 9: 612–620.

Czernik A, Camilleri M, Pittelkow MR and Grando SA (2011) Paraneoplastic autoimmune multiorgan syndrome: 20 years after. International Journal of Dermatology 50: 905–914.

Djinovic‐Carugo K, Gautel M, Ylanne J and Young P (2002) The spectrin repeat: a structural platform for cytoskeletal protein assemblies. Federation of European Biochemical Societies Letters 513: 119–123.

Edvardson S, Cinnamon Y, Jalas C et al. (2012) Hereditary sensory autonomic neuropathy caused by a mutation in dystonin. Annals of Neurology 71: 569–572.

Elliott CE, Becker B, Oehler S et al. (1997) Plectin transcript diversity: identification and tissue distribution of variants with distinct first coding exons and rodless isoforms. Genomics 42: 115–125.

Fontao L, Favre B, Riou S et al. (2003) Interaction of the bullous pemphigoid antigen 1 (BP230) and desmoplakin with intermediate filaments is mediated by distinct sequences within their COOH terminus. Molecular Biology of the Cell 14: 1978–1992.

Fuchs P, Zorer M, Rezniczek GA et al. (1999) Unusual 5′ transcript complexity of plectin isoforms: novel tissue‐specific exons modulate actin binding activity. Human Molecular Genetics 8: 2461–2472.

Geerts D, Fontao L, Nievers MG et al. (1999) Binding of integrin alpha6beta4 to plectin prevents plectin association with F‐actin but does not interfere with intermediate filament binding. Journal of Cell Biology 147: 417–434.

Giudice GJ, Emery DJ, Zelickson BD et al. (1993) Bullous pemphigoid and herpes gestationis autoantibodies recognize a common non‐collagenous site on the BP180 ectodomain. Journal of Immunology 151: 5742–5750.

Groves RW, Liu L, Dopping‐Hepenstal PJ et al. (2010) A homozygous nonsense mutation within the dystonin gene coding for the coiled‐coil domain of the epithelial isoform of BPAG1 underlies a new subtype of autosomal recessive epidermolysis bullosa simplex. Journal of Investigative Dermatology 130: 1551–1557.

Gundesli H, Talim B, Korkusuz P et al. (2010) Mutation in exon 1f of PLEC, leading to disruption of plectin isoform 1f, causes autosomal‐recessive limb‐girdle muscular dystrophy. American Journal of Human Genetics 87: 834–841.

Huang Y, Li J and Zhu X (2009) Detection of anti‐envoplakin and anti‐periplakin autoantibodies by ELISA in patients with paraneoplastic pemphigus. Archives in Dermatological Research 301: 703–709.

Jefferson JJ, Leung CL and Liem RK (2006) Dissecting the sequence specific functions of alternative N‐terminal isoforms of mouse bullous pemphigoid antigen 1. Experimental Cell Research 312: 2712–2725.

Jonkman MF, Pasmooij AM, Pasmans SG et al. (2005) Loss of desmoplakin tail causes lethal acantholytic epidermolysis bullosa. American Journal of Human Genetics 77: 653–660.

Kalinin AE, Idler WW, Marekov LN et al. (2004) Co‐assembly of envoplakin and periplakin into oligomers and Ca(2+)‐dependent vesicle binding: implications for cornified cell envelope formation in stratified squamous epithelia. Journal of Biological Chemistry 279: 22773–22780.

Karashima T and Watt FM (2002) Interaction of periplakin and envoplakin with intermediate filaments. Journal of Cell Science 115: 5027–5037.

Kazerounian S, Uitto J and Aho S (2002) Unique role for the periplakin tail in intermediate filament association: specific binding to keratin 8 and vimentin. Experimental Dermatology 11: 428–438.

Kiss M, Husz S, Janossy T et al. (2005) Experimental bullous pemphigoid generated in mice with an antigenic epitope of the human hemidesmosomal protein BP230. Journal of Autoimmunity 24: 1–10.

Korenbaum E and Rivero F (2002) Calponin homology domains at a glance. Journal of Cell Science 115: 3543–3545.

Koss‐Harnes D, Hoyheim B, Anton‐Lamprecht I et al. (2002) A site‐specific plectin mutation causes dominant epidermolysis bullosa simplex Ogna: two identical de novo mutations. Journal of Investigative Dermatology 118: 87–93.

Koster J, Geerts D, Favre B, Borradori L and Sonnenberg A (2003) Analysis of the interactions between BP180, BP230, plectin and the integrin alpha6beta4 important for hemidesmosome assembly. Journal of Cell Science 116: 387–399.

Koster J, van Wilpe S, Kuikman I, Litjens SH and Sonnenberg A (2004) Role of binding of plectin to the integrin beta4 subunit in the assembly of hemidesmosomes. Molecular Biology of the Cell 15: 1211–1223.

Leung CL, Sun D, Zheng M, Knowles DR and Liem RK (1999) Microtubule actin cross‐linking factor (MACF): a hybrid of dystonin and dystrophin that can interact with the actin and microtubule cytoskeletons. Journal of Cell Biology 147: 1275–1286.

Li J, Bu DF, Huang YC and Zhu XJ (2009) Role of autoantibodies against the linker subdomains of envoplakin and periplakin in the pathogenesis of paraneoplastic pemphigus. Chinese Medical Journal 122: 486–495.

Lin CM, Chen HJ, Leung CL, Parry DA and Liem RK (2005) Microtubule actin crosslinking factor 1b: a novel plakin that localizes to the Golgi complex. Journal of Cell Science 118: 3727–3738.

Liu Z, Diaz LA, Troy JL et al. (1993) A passive transfer model of the organ‐specific autoimmune disease, bullous pemphigoid, using antibodies generated against the hemidesmosomal antigen, BP180. Journal of Clinical Investigation 92: 2480–2488.

Nakamura H, Sawamura D, Goto M et al. (2005) Epidermolysis bullosa simplex associated with pyloric atresia is a novel clinical subtype caused by mutations in the plectin gene (PLEC1). Journal of Molecular Diagnostics 7: 28–35.

Natsuga K, Nishie W, Akiyama M et al. (2010) Plectin expression patterns determine two distinct subtypes of epidermolysis bullosa simplex. Human Mutation 31: 308–316.

Nishie W, Sawamura D, Goto M et al. (2007) Humanization of autoantigen. Nature Medicine 13: 378–383.

de Pereda JM, Lillo MP and Sonnenberg A (2009) Structural basis of the interaction between integrin alpha6beta4 and plectin at the hemidesmosomes. European Molecular Biology Organization Journal 28: 1180–1190.

Protonotarios N and Tsatsopoulou A (2004) Naxos disease and Carvajal syndrome: cardiocutaneous disorders that highlight the pathogenesis and broaden the spectrum of arrhythmogenic right ventricular cardiomyopathy. Cardiovascular Pathology 13: 185–194.

Seifert GJ, Lawson D and Wiche G (1992) Immunolocalization of the intermediate filament‐associated protein plectin at focal contacts and actin stress fibers. European Journal of Cell Biology 59: 138–147.

Skalli O, Jones JC, Gagescu R and Goldman RD (1994) IFAP 300 is common to desmosomes and hemidesmosomes and is a possible linker of intermediate filaments to these junctions. Journal of Cell Biology 125: 159–170.

Smith FJ, Eady RA, Leigh IM et al. (1996) Plectin deficiency results in muscular dystrophy with epidermolysis bullosa. Nature Genetics 13: 450–457.

Spazierer D, Raberger J, Gross K, Fuchs P and Wiche G (2008) Stress‐induced recruitment of epiplakin to keratin networks increases their resistance to hyperphosphorylation‐induced disruption. Journal of Cell Science 121: 825–833.

Stappenbeck TS, Lamb JA, Corcoran CM and Green KJ (1994) Phosphorylation of the desmoplakin COOH terminus negatively regulates its interaction with keratin intermediate filament networks. Journal of Biological Chemistry 269: 29351–29354.

Sterk LM, Geuijen CA, Oomen LC et al. (2000) The tetraspan molecule CD151, a novel constituent of hemidesmosomes, associates with the integrin alpha6beta4 and may regulate the spatial organization of hemidesmosomes. Journal of Cell Biology 149: 969–982.

Sun D, Leung CL and Liem RK (2001) Characterization of the microtubule binding domain of microtubule actin crosslinking factor (MACF): identification of a novel group of microtubule associated proteins. Journal of Cell Science 114: 161–172.

Svitkina TM, Verkhovsky AB and Borisy GG (1996) Plectin sidearms mediate interaction of intermediate filaments with microtubules and other components of the cytoskeleton. Journal of Cell Biology 135: 991–1007.

Walko G, Vukasinovic N, Gross K et al. (2011) Targeted proteolysis of plectin isoform 1a accounts for hemidesmosome dysfunction in mice mimicking the dominant skin blistering disease EBS‐Ogna. Public Library of Science Genetics 7: e1002396.

Whittock NV, Wan H, Morley SM et al. (2002) Compound heterozygosity for non‐sense and mis‐sense mutations in desmoplakin underlies skin fragility/woolly hair syndrome. Journal of Investigative Dermatology 118: 232–238.

Yang Z, Bowles NE, Scherer SE et al. (2006) Desmosomal dysfunction due to mutations in desmoplakin causes arrhythmogenic right ventricular dysplasia/cardiomyopathy. Circulation Research 99: 646–655.

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.

Related Sub-Topics:

Mutational Mechanisms of Genetic Disease | Specific Genetic Disorders | Cell Cytoskeleton | Proteins: Structure, Function, Metabolism | Cell Structure | Cell Membranes
Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

Article Title: Plakin Proteins, Hemidesmosomes and Human Disease
 
How to Cite close
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]