Discovery of a novel ligand that modulates the protein-protein interactions of the AAA+ superfamily oncoprotein reptin
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Developing approaches to discover protein-protein interactions (PPIs) remains a fundamental challenge. A chemical biology platform is applied here to identify novel PPIs for the AAA+ superfamily oncoprotein reptin. An in silico screen coupled with chemical optimization provided Liddean, a nucleotide-mimetic which modulates reptin’s oligomerization status, protein-binding activity and global conformation. Combinatorial peptide phage library screening of Liddean-bound reptin with next generation sequencing identified interaction motifs including a novel reptin docking site on the p53 tumor suppressor protein. Proximity ligation assays demonstrated that endogenous reptin forms a predominantly cytoplasmic complex with its paralog pontin in cancer cells and Liddean promotes a shift of this complex to the nucleus. An emerging view of PPIs in higher eukaryotes is that they occur through a striking diversity of linear peptide motifs. The discovery of a compound that alters reptin’s protein interaction landscape potentially leads to novel avenues for therapeutic development.
Healy , A , Houston , D R , Remnant , L , Huart , A-S , Brychtova , V , Maslon , M M , Meers , O , Muller , P , Krecji , A , Blackburn , E M , Vojtesek , B , Hernychova , L , Walkinshaw , M D , Westwood , N J & Hupp , T 2015 , ' Discovery of a novel ligand that modulates the protein-protein interactions of the AAA+ superfamily oncoprotein reptin ' Chemical Science , vol In press . DOI: 10.1039/C4SC03885A
Copyright 2015 the Authors. This Open Access Article is licensed under a Creative Commons Attribution 3.0 Unported Licence (http://creativecommons.org/licenses/by/3.0/).
Financial support for this project was provided by Cancer Research UK (CRUK grant C21383/A6950). CRUK C483/A10706 and C483/A8033; EPSRC EP/F500421/1 doctoral training centre in cell and proteomic technologies; GACR P206/12/G151 and the state budget of the Czech Republic (LO1413).
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