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Desmosome Structure, Composition and Function ⁎ David Garrod A, Martyn Chidgey B

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Desmosome Structure, Composition and Function ⁎ David Garrod A, Martyn Chidgey B CORE Metadata, citation and similar papers at core.ac.uk Provided by Elsevier - Publisher Connector Available online at www.sciencedirect.com Biochimica et Biophysica Acta 1778 (2008) 572–587 www.elsevier.com/locate/bbamem Review Desmosome structure, composition and function ⁎ David Garrod a, Martyn Chidgey b, a Faculty of Life Sciences, University of Manchester, Michael Smith Building, Oxford Road, Manchester M13 9PT, UK b Division of Medical Sciences, University of Birmingham, Clinical Research Block, Queen Elizabeth Hospital, Birmingham B15 2TH, UK Received 24 May 2007; received in revised form 19 July 2007; accepted 20 July 2007 Available online 9 August 2007 Abstract Desmosomes are intercellular junctions of epithelia and cardiac muscle. They resist mechanical stress because they adopt a strongly adhesive state in which they are said to be hyper-adhesive and which distinguishes them from other intercellular junctions; desmosomes are specialised for strong adhesion and their failure can result in diseases of the skin and heart. They are also dynamic structures whose adhesiveness can switch between high and low affinity adhesive states during processes such as embryonic development and wound healing, the switching being signalled by protein kinase C. Desmosomes may also act as signalling centres, regulating the availability of signalling molecules and thereby participating in fundamental processes such as cell proliferation, differentiation and morphogenesis. Here we consider the structure, composition and function of desmosomes, and their role in embryonic development and disease. © 2007 Elsevier B.V. All rights reserved. Contents 1. Introduction .............................................................. 573 1.1. The strength of the desmosome–intermediate filament complex ................................ 573 1.2. Desmosomes resist mechanical stress because they are hyper-adhesive . ........................... 574 1.3. Hyper-adhesiveness can be modulated by intracellular signalling ............................... 574 1.4. Desmosome structure—can it account for hyper-adhesion?................................... 574 1.5. Significance of hyper-adhesion for embryonic development and the experimental approach to epithelial cell behaviour . 576 2. Desmosome composition ....................................................... 576 2.1. Desmoplakin .......................................................... 576 2.2. Armadillo proteins ....................................................... 576 2.3. Desmosomal cadherins ..................................................... 578 2.4. Perp .............................................................. 578 2.5. Corneodesmosin ........................................................ 578 2.6. Interactions between desmosomal constituents ......................................... 579 2.6.1. (a) Adhesive binding ................................................. 579 2.6.2. (b) Intracellular binding ................................................ 579 3. Desmosome function ......................................................... 580 3.1. Loss of desmosomal adhesion can disrupt tissue integrity ................................... 580 3.2. Abnormalities in tissue differentiation and morphogenesis occur in some diseases of desmosomes .............. 581 3.3. Desmosomes can influence intracellular signal transduction pathways . ........................... 582 3.4. Desmosomes in embryonic development............................................ 583 ⁎ Corresponding author. E-mail addresses: [email protected] (D. Garrod), [email protected] (M. Chidgey). 0005-2736/$ - see front matter © 2007 Elsevier B.V. All rights reserved. doi:10.1016/j.bbamem.2007.07.014 D. Garrod, M. Chidgey / Biochimica et Biophysica Acta 1778 (2008) 572–587 573 4. Conclusion .............................................................. 583 References ................................................................. 583 1. Introduction into three components, two intracellular and one intercellular. Intracellularly there are the intermediate filaments, and the Desmosomes are intercellular junctions that provide strong linkage between the intermediate filaments and the desmosomal adhesion between cells. Because they also link intracellularly to adhesion molecules; intercellularly there is the adhesive bond the intermediate filament cytoskeleton they form the adhesive provided by the desmosomal adhesion molecules (Fig. 1). The bonds in a network that gives mechanical strength to tissues. two intracellular components of the DIFC have been much Thus desmosomes are particularly abundant in tissues such as studied but little is known about the mechanism of adhesive epidermis and myocardium that are continually assailed by binding. mechanical forces. When desmosomal adhesion fails, as in Each of these three components of the DIFC must be equally certain genetic and autoimmune diseases, tissues that are capable of resisting mechanical disruption and failure of any of subjected to mechanical stress may fall apart. The desmosome– them is disastrous as illustrated by certain human diseases of the intermediate filament complex (DIFC) is a network or scaf- epidermis (Fig. 1). Failure of the intermediate filaments is found folding that maintains the integrity of such tissues. in epidermolysis bullosa simplex, an epidermal blistering dis- ease of varying severity caused by mutations in the genes 1.1. The strength of the desmosome–intermediate filament encoding the basal epidermal keratins 5 and 14 [1]. These mu- complex tations cause disruption of the keratin filaments and consequent stress-induced rupture of basal epidermal cells. The linkage In any structure strength is dependent upon the strength of its between the intermediate filaments and the desmosomal individual components. Thus there is no use having strong adhesion molecules is mediated by desmoplakin and the scaffolding poles if the scaffold couplings are weak, and a chain armadillo proteins plakoglobin and plakophilin. Failure in one is only as strong as its weakest link. The DIFC may be divided part of this link is seen in the only case so far reported of lethal Fig. 1. The desmosome-intermediate filament complex showing some of the key links and diseases that weaken them. The interactions between the complexof proteins within the outer dense plaque (ODP) is not fully understood, and plakoglobin (not shown) may contribute to the link in the chain between desmoplakin and the desmosomal cadherins. Alternatively desmoplakin may interact with the desmosomal cadherins directly, with plakophilin and plakoglobin mediating lateral interactions (see text). PM, plasma membrane. 574 D. Garrod, M. Chidgey / Biochimica et Biophysica Acta 1778 (2008) 572–587 acantholytic epidermolysis bullosa [2]. Mutations that caused destroyed by scratch wounding cells at the wound edge rapidly deletion of the C-terminus of desmoplakin resulted in de- reverted to calcium dependence, an effect that was propagated tachment of the keratin filaments and severe disruption of the into the monolayer. We showed that switching from calcium epidermis during birth. Failure in another part is shown by the dependence to independence could be rapidly achieved (in genetic disease ectodermal dysplasia/skin fragility syndrome, in minutes) by inhibiting conventional isoforms of protein kinase C which plakophilin-1 mutations cause detachment of intermedi- (PKC) and the reverse switch by PKC activation [5]. In MDCK ate filaments and desmoplakin from the desmosome [3]. Failure cells PKC alpha was the isoform involved. In wound edge epi- of desmosomal adhesive binding resulting in separation of dermis, PCK alpha became associated with desmosomal plaques desmosomal halves in the intercellular region and consequent [6]. epidermal blistering is seen in pemphigus in which the des- In a recent study with the human keratinocyte cell line mosomal cadherins desmoglein (Dsg) 1 and 3 are targeted by HaCaT, we showed that neither slow acquisition of calcium autoantibodies [4]. independence by confluent cells nor rapid switching between the alternative states with a PKC activator or inhibitor involved 1.2. Desmosomes resist mechanical stress because they are any change, qualitative or quantitative, in the composition of hyper-adhesive desmosomes [7]. This accorded with previous observations that switching could be achieved in the absence of protein synthesis It has recently become clear how desmosomal adhesiveness [5]. These results indicate that the change is produced by gen- contributes to the strength of the DIFC. Desmosomes are able to eration of an “inside-out” signal by PKC. adopt two alternative adhesive states that differ in adhesive affinity [5–7]. We refer to the more strongly adhesive des- 1.4. Desmosome structure—can it account for hyper-adhesion? mosomes as “hyper-adhesive” to distinguish this state from the weaker condition. Hyper-adhesiveness is characterised experi- Desmosomes have a quite characteristic highly organised, mentally by calcium independence, that is resistance of desmo- electron dense structure. They are less than 1 μm in diameter somes to disruption by chelating agents. This is very surprising and consist of a central core region that spans the intercellular because the desmosomal adhesion molecules, desmocollin and space between apposing cells and separates two identical desmoglein, are members of the cadherin family of calcium cytoplasmic plaques that are associated with the intermediate
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