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Desmosome Identification of Desmoglein as a Cadherin and Analysis of Desmoglein Domain Structure Ken Ishii1 1Department of Dermatology, University of Pennsylvania, Philadelphia, Pennsylvania, USA. Correspondence: Dr Ken Ishii, E-mail: [email protected] Published online 30 January 2007. doi:10.1038/sj.skinbio.6250001

In the 1980s and early 1990s, the extracellular subdomains in cadherins the desmosome, desmocollin (Collins ability to clone complementary DNA and that, similar to those units, con- et al., 1991). cDNA cloning of desmo- (cDNA) resulted in great advances tained putative calcium-binding sites. collin indicated that it also belonged in cell biology, including our under- The cytoplasmic domain of desmoglein, to the cadherin family. The unique standing of cell adhesion. Cloning the although it contained a subdomain aspect of desmocollin was that the cDNA encoding desmosomal mole- (termed the intracellular cadherin seg- cytoplasmic domain contained a cules, and the determination of their ment or ICS) that was homologous to longer “a” form and a shorter “b” deduced amino-acid sequences, pro- a cytoplasmic subdomain of cadherin, form, produced by alternative splicing vided novel insights into their structure significantly differed in that it was lon- of mRNA. and function. ger than that of cadherins. In addition To date, four isoforms of desmoglein It had been shown by various to the ICS subdomain, desmoglein (Dsg1–4) and three isoforms of desmo- biochemical and immunochemical contained a proline-rich linker (IPL) collin (Dsc1–3) have been identified, techniques that desmosomal proteins and a terminal repeating unit domain each arising from a different gene. consist of plaque proteins inside the (RUD). Although the ICS domain has The genes are clustered on the q arm cell and transmembrane glycopro- been shown to bind various intracellu- of chromosome 18 for humans (Kljuic teins. For desmosomal transmembrane lar molecules, such as plakoglobin, the et al., 2003). Because of their homol- glycoproteins, Koch et al. (1990) first function of the additional subdomains ogies to classical cadherins, these isolated and characterized the cDNA of desmoglein remains unclear. glycoproteins are now termed “desmo- encoding desmoglein in 1990. Using Progress, by cDNA cloning, was somal cadherins”. monoclonal antibodies against des- also made in characterizing the other The cDNA cloning of desmoglei- moglein, they screened cDNA expres- major transmembrane molecule of ns and, subsequently, desmocollins, sion libraries constructed from bovine muzzle epithelial mRNA. The major scientific advance from this work was EC1 EC2 EC3 EC4 EA IA ICS IPL RUD DTD that the deduced amino-acid sequenc- Desmoglein es of their isolated clones showed high homology to cadherins, which had ICS already been shown to be calcium- EC1 EC2 EC3 EC4 EA IA a form dependent cell adhesion molecules. Desmocollin Thus, they identified desmoglein as b form a member of the cadherin supergene family of cell adhesion molecules. Similar to classic cadherins such EC1 EC2 EC3 EC4 EAIA ICS as E- and N-cadherins, they, and sub- Classic cadherin sequently others, showed that desmo- glein is a type I transmembrane protein with an amino-terminal extracellu- Extracellular domain TM Intracellular domain lar domain, a single transmembrane spanning region, and a carboxy-ter- Figure 1. Structure of desmosomal cadherins (desmoglein and the two splice forms of desmocollin) and the classical cadherin E-cadherin. EC1–EC4, four extracellular cadherin-typical repeats; EA, extracellular minal cytoplasmic domain (Figure 1). anchor domain; TM, transmembrane domain; IA, intracellular anchor domain; ICS, intracellular cadherin- The extracellular domain was shown specific domain. Desmoglein contains an additional intracellular domain: IPL, proline-rich linker domain; to contain four subdomain repeating RUD, repeating unit domain; DTD, desmoglein-specific terminal domain. (Adapted from Amagai, 1996, units that have homology to similar with permission from Elsevier.)

E6 JANUARY 2007 MILESTONES | CUTANEOUS BIOLOGY provided the first evidence that these TO CITE THIS ARTICLE adhesion molecules with heterogeneous cytoplasmic domains. J Cell Biol 113:381–91 molecules could be calcium-depen- Ishii K (2007) Identification of desmoglein as dent cell adhesion molecules and a cadherin and analysis of desmoglein domain Kljuic A, Bazzi H, Sundberg JP, Martinez-Mir A, might provide the adhesive component structure. J Invest Dermatol 127:E6–7 O’Shaughnessy R, Mahoney MG et al. (2003) Desmoglein 4 in hair follicle differentiation and of desmosomes. Their cloning provid- epidermal adhesion: evidence from inherited ed cell biologists the tools necessary REFERENCES hypotrichosis and acquired pemphigus vulgaris. to test these hypotheses directly and to Amagai M (1996) Pemphigus: autoimmunity to Cell 113:249–60 study the involvement of these desmo- epidermal cell adhesion molecules. Adv Dermatol Koch PJ, Walsh MJ, Schmelz M, Goldschmidt MD, 11:319–52 somal cadherins in disease. Zimbelmann R, Franke WW (1990). Identification Collins JE, Legan PK, Kenny TP, MacGarvie of desmoglein, a constitutive desmosomal ACKNOWLEDGMENT J, Holton JL, Garrod DR (1991) Cloning and glycoprotein, as a member of the cadherin I am grateful to Dr. John Stanley for helpful sequence analysis of desmosomal glycoproteins 2 family of cell adhesion molecules. Eur J Cell Biol comments. and 3 (desmocollins): cadherin-like desmosomal 53:1–12.

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