Self-regulation of functional pathways by motifs inside the disordered tails of beta-catenin

Bi Zhao, Bin Xue

Beta-catenin has two major functions: coordinating cell-cell adhesion by interacting with cadherin in cadherin junction formation pathway; and regulating gene expression through Wnt signaling pathway. Accomplishing these two functions requires synergistic action of various sequential regions of the same beta-Catenin molecule, including the N-terminal tail, the middle armadillo domain, and the C-terminal tail. Although the middle armadillo domain is the major functional unit of beta-Catenin, the involvement of tails in the regulation of interaction between beta-Catenin and its partners has been well observed. Nonetheless, the regulatory processes of both tails are still elusive. In addition, it is interesting to note that the three sequential regions have different structural features: The middle armadillo domain is structured, but both N- and C-terminal tails are disordered. This observation leads to another important question on the functions and mechanisms of disordered tails, which is also largely unknown. In this study, we focused on the characterization of sequential, structural, and functional features of the disordered tails of beta-Catenin. We identified multiple functional motifs and conserved sequence motifs in the disordered tails, discovered the correlation between cancer-associated mutations and functional motifs, explored the abundance of protein intrinsic disorder in the interactomes of beta-Catenin, and elaborated a working model on the regulatory roles of disordered tails in the functional pathways of beta-Catenin. Disordered tails of beta-Catenin contain multiple functional motifs. These motifs interact with each other and the armadillo domain of beta-catenin to regulate the function of beta-Catenin in both cadherin junction formation pathway and Wnt signaling pathway.