AUTHOR=Rowling Pamela J. E. , Murton Ben L. , Du Zhen , Itzhaki Laura S. 

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

JOURNAL=Frontiers in Molecular Biosciences

VOLUME=Volume 9 - 2022

YEAR=2022

URL=https://www.frontiersin.org/journals/molecular-biosciences/articles/10.3389/fmolb.2022.896493

DOI=10.3389/fmolb.2022.896493

ISSN=2296-889X

ABSTRACT=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 beta-catenin acts as the signal transducer in this pathway. Here we investigate the interaction between beta-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 ‘beta-catenin destruction complex’, which drives beta-catenin degradation via the ubiquitin-proteasome pathway. Mutations and truncations in APC, resulting in loss of APC function and hence elevated beta-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 beta-catenin. Here we explore the multivalent nature of the interaction of beta-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 beta-catenin-binding subdomains of APC.