Discovery of a novel ligand that modulates the protein-protein interactions of the AAA+ superfamily oncoprotein reptin

Alan Healy, Douglas R. Houston, Lucy Remnant, Anne-Sophie Huart, Veronika Brychtova, Magda M. Maslon, Olivia Meers, Petr Muller, Adam Krecji, Elizabeth M. Blackburn, B. Vojtesek, Lenka Hernychova, M. D. Walkinshaw, Nicholas James Westwood, Ted Hupp

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Abstract

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.
Original languageEnglish
JournalChemical Science
VolumeIn press
Early online date20 Mar 2015
DOIs
Publication statusPublished - 2015

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