The 15-aa repeat region of Adenomatous polyposis coli is intrinsically disordered and retains conformational flexibility upon binding β-catenin
Rudeen, Aaron J.
Douglas, Justin T.
McDonald, W. Hayes
Lamb, Audrey L.
Neufeld, Kristi L.
American Chemical Society
Scholarly/refereed, author accepted manuscript
Copyright © 2020 American Chemical Society.
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The tumor suppressor Adenomatous polyposis coli (APC) is a large, multidomain protein with many identified cellular functions. The best characterized role of APC is to scaffold a protein complex that negatively regulates Wnt signaling via β-catenin destruction. This destruction is mediated by β-catenin binding to centrally located 15- and 20-amino acid repeat regions of APC. More than 80% of cancers of the colon and rectum present with an APC mutation. Most carcinomas with mutant APC express a truncated APC protein that retains the ∼200-amino acid long′ 15-amino acid repeat region′. This study demonstrates that the 15-amino acid repeat region of APC is intrinsically disordered. We investigated the backbone dynamics in the presence of β-catenin and predicted residues that may contribute to transient secondary features. This study reveals that the 15-amino acid region of APC retains flexibility upon binding β-catenin and that APC does not have a single, observable “highest-affinity” binding site for β-catenin. This flexibility potentially allows β-catenin to be more readily captured by APC and then remain accessible to other elements of the destruction complex for subsequent processing.
This document is the Accepted Manuscript version of a Published Work that appeared in final form in Biochemistry, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see https://doi.org/10.1021/acs.biochem.0c00479.
Rudeen, A. J., Douglas, J. T., Xing, M., McDonald, W. H., Lamb, A. L., & Neufeld, K. L. (2020). The 15-Amino Acid Repeat Region of Adenomatous Polyposis Coli Is Intrinsically Disordered and Retains Conformational Flexibility upon Binding β-Catenin. Biochemistry, 59(41), 4039–4050. https://doi.org/10.1021/acs.biochem.0c00479
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