Multivalent Interaction of Beta-Catenin With its Intrinsically Disordered Binding Partner Adenomatous Polyposis Coli

• Published in: Frontiers in molecular biosciences 2022-06, Vol.9, p.896493-896493
• Main Authors: Rowling, Pamela J E, Murton, Ben L, Du, Zhen, Itzhaki, Laura S
• Format: Article
• Language: English
• Subjects: adenomatous polyposis coli (APC); beta-catenin (β-catenin); fuzzy binding; intrinsically disordered protein; Molecular Biosciences; multivalency; protein-protein interaction (PPI)
• ISSN: 2296-889X; 2296-889X
• DOI: 10.3389/fmolb.2022.896493

The Wnt signalling pathway plays key roles in cell proliferation, differentiation and fate decisions in embryonic development and maintenance of adult tissues, and the twelve Armadillo (ARM) repeat-containing protein β-catenin acts as the signal transducer in this pathway. Here we investigate the interaction between β-catenin's ARM repeat domain and the intrinsically disordered protein adenomatous polyposis coli (APC). APC is a giant multivalent scaffold that brings together the different components of the so-called "β-catenin destruction complex", which drives β-catenin degradation the ubiquitin-proteasome pathway. Mutations and truncations in APC, resulting in loss of APC function and hence elevated β-catenin levels and upregulation of Wnt signalling, are associated with numerous cancers including colorectal carcinomas. APC has a long intrinsically disordered region (IDR) that contains a series of 15-residue and 20-residue binding regions for β-catenin. Here we explore the multivalent nature of the interaction of β-catenin with the highest affinity APC repeat, both at equilibrium and under kinetic conditions. We use a combination of single-site substitutions, deletions and insertions to dissect the mechanism of molecular recognition and the roles of the three β-catenin-binding subdomains of APC.