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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. Xing, Minli McDonald, W. Hayes Lamb, Audrey L. Neufeld, Kristi L.
Rudeen, Aaron J.
Douglas, Justin T.
Xing, Minli
McDonald, W. Hayes
Lamb, Audrey L.
Neufeld, Kristi L.
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Abstract
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.
Description
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.
Date
2020-10-20
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American Chemical Society
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Keywords
APC, Intrinsically Disordered Protein, β-catenin, Cancer Biology, Stoichiometry, NMR, Structure-Function
Citation
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