Molecular Mechanism of the cell cell adhesion by atypical cadherin 23

Abstract

Cadherins mediate the cell-cell junctions in multicellular organisms. Essential cellular newlinefunctions like cell-migration, differentiation, and morphogenesis that require tailoring of the newlinecell-cell junctions are achieved by regulating the expression of cadherins. Among cadherins, newlinenon-classical cadherins comprise ~80% of cadherin proteins in the family. However, little is newlineknown on their participation in cell-adhesion. Cadherin-23 (Cdh23), long non-classical newlinecadherin with 27 extracellular (EC) domains has recently been known to mediate cell-cell newlinejunctions through homophilic interactions, and its expression is regulated during cancer newlinemetastasis. Data from The Cancer Genome Atlas indicated a key correlation between Cdh23 newlineexpression and patient survival, lower the expression poor is the survival of patients. Further, newlinein-vitro studies have measured a stronger aggregation-propensity of Cdh23 than one of the newlinetypical cadherins. While the mechanism of homophilic interaction for classical cadherins is newlineknown, the homodimer structure for Cdh23 is not yet resolved. We deciphered the unique trans- newlinehomodimer structure of Cdh23 which consists of two electrostatic-based interfaces extended newlineup to two terminal domains (EC1-2). This unique interface is robust with a dissociation newlineconstant, 18±4 µM and an off-rate of ~8x10-4 s -1 . Next, we measured the role of the remaining newline25 non-interacting EC-domains on the homophilic trans-interactions. With the help of domain newlinedeletion mutants, we showed that the flexibility exhibited by EC-domains increases with the newlinenumber of domains. In-cellulo aggregation assays also showed faster aggregation of cells with newlineincreasing domain numbers. From single-molecule force spectroscopy studies, we also newlineobserved that lifetime for the trans-interactions increases with the number of domains.