Abstract
Cadherins are single pass transmembrane proteins that mediate Ca(2+)-dependent homophilic cell-cell adhesion by linking the cytoskeletons of adjacent cells. In adherens junctions, the cytoplasmic domain of cadherins bind to beta-catenin, which in turn binds to the actin-associated protein alpha-catenin. The physical properties of the E-cadherin cytoplasmic domain and its interactions with beta-catenin have been investigated. Proteolytic sensitivity, tryptophan fluorescence, circular dichroism, and (1)H NMR measurements indicate that murine E-cadherin cytoplasmic domain is unstructured. Upon binding to beta-catenin, the domain becomes resistant to proteolysis, suggesting that it structures upon binding. Cadherin-beta-catenin complex stability is modestly dependent on ionic strength, indicating that, contrary to previous proposals, the interaction is not dominated by electrostatics. Comparison of 18 cadherin sequences indicates that their cytoplasmic domains are unlikely to be structured in isolation. This analysis also reveals the presence of PEST sequences, motifs associated with ubiquitin/proteosome degradation, that overlap the previously identified beta-catenin-binding site. It is proposed that binding of cadherins to beta-catenin prevents recognition of degradation signals that are exposed in the unstructured cadherin cytoplasmic domain, favoring a cell surface population of catenin-bound cadherins capable of participating in cell adhesion.
Highlights
Cadherins are single pass transmembrane proteins that mediate Ca2؉-dependent homophilic cell-cell adhesion by linking the cytoskeletons of adjacent cells
It is proposed that binding of cadherins to -catenin prevents recognition of degradation signals that are exposed in the unstructured cadherin cytoplasmic domain, favoring a cell surface population of cateninbound cadherins capable of participating in cell adhesion
Recombinant Cadherin Cytoplasmic Domains Are Not Folded in Isolation—Fluorescence, circular dichroism, and proton NMR were used to characterize the folded state of recombinant E-cadherin and DE-cadherin cytoplasmic domains
Summary
The cytoplasmic domain of cadherins bind to -catenin, which in turn binds to the actin-associated protein ␣-catenin. Comparison of 18 cadherin sequences indicates that their cytoplasmic domains are unlikely to be structured in isolation This analysis reveals the presence of PEST sequences, motifs associated with ubiquitin/proteosome degradation, that overlap the previously identified -catenin-binding site. Tyrosine kinases target several adherens junction components that could modulate junctional stability, including -catenin [21] and the arm repeat protein p120ctn [22,23,24], which binds the cadherin cytoplasmic domain at a site distinct from -catenin [25, 26]. The -catenin binding sequences in LEF-1 and APC are largely electronegative, and recent mutagenesis studies have indicated that they bind within the positively charged groove formed by the armadillo repeat region of -catenin [30]. It is proposed that these properties are associated with the regulation of cadherin turnover and cellular adhesiveness
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