Desmosomal hyper-adhesion is accompanied with enhanced binding strength of desmoglein 3 molecules

Abstract Intercellular adhesion of keratinocytes depends critically on desmosomes which, during maturation, acquire a hyper-adhesive and thus Ca2+-independent state. Here, we investigated the roles of desmoglein (Dsg) 3 and plakophilins (Pkps) in hyper-adhesion. Atomic force microscopy (AFM) single molecule force mappings revealed increased Dsg3 molecules but not Dsg1 molecules binding strength in murine keratinocytes. However, keratinocytes lacking Dsg3, Pkp1 or 3 revealed reduced Ca2+-independency. In addition, Pkp1 or 3 deficient keratinocytes did not exhibit changes in Dsg3 binding on the molecular level. Further, wild-type (wt) keratinocytes showed increased levels of Dsg3-oligomers during acquisition of hyper-adhesion and Pkp1-deficiency abolished formation of Ca2+-independent Dsg3-oligomers. In concordance, immunostaining for Dsg1 but not for Dsg3 was reduced after 24h of Ca2+-chelation in an ex-vivo human skin model, suggesting that desmosomal cadherins may have different roles during acquisition of hyper-adhesion. Taken together, these data indicate that hyper-adhesion may not be a state acquired by entire desmosomes but rather is paralleled by enhanced binding of specific desmoglein isoforms such as Dsg3, a process for which plaque proteins including Pkp 1 and 3 are required as well.