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 Krejci, Elizabeth A. Blackburn, Borek Vojtesek, Lenka Hernychova, Malcolm D. Walkinshaw, Nicholas J. Westwood, Ted R. Hupp

    Research output: Contribution to journalArticle

    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 (US)
    Pages (from-to)3109-3116
    Number of pages8
    JournalChemical Science
    Volume6
    Issue number5
    DOIs
    StatePublished - May 1 2015

    Fingerprint

    Oncogene Proteins
    Ligands
    Proteins
    Tumor Suppressor Protein p53
    Oligomerization
    Peptides
    Bacteriophages
    Conformations
    Assays
    Screening
    Thermodynamic properties
    Nucleotides
    Cells

    ASJC Scopus subject areas

    • Chemistry(all)

    Cite this

    Healy, A., Houston, D. R., Remnant, L., Huart, A. S., Brychtova, V., Maslon, M. M., ... Hupp, T. R. (2015). Discovery of a novel ligand that modulates the protein-protein interactions of the AAA+ superfamily oncoprotein reptin. Chemical Science, 6(5), 3109-3116. https://doi.org/10.1039/c4sc03885a

    Discovery of a novel ligand that modulates the protein-protein interactions of the AAA+ superfamily oncoprotein reptin. / Healy, Alan; Houston, Douglas R.; Remnant, Lucy; Huart, Anne Sophie; Brychtova, Veronika; Maslon, Magda M.; Meers, Olivia; Muller, Petr; Krejci, Adam; Blackburn, Elizabeth A.; Vojtesek, Borek; Hernychova, Lenka; Walkinshaw, Malcolm D.; Westwood, Nicholas J.; Hupp, Ted R.

    In: Chemical Science, Vol. 6, No. 5, 01.05.2015, p. 3109-3116.

    Research output: Contribution to journalArticle

    Healy, A, Houston, DR, Remnant, L, Huart, AS, Brychtova, V, Maslon, MM, Meers, O, Muller, P, Krejci, A, Blackburn, EA, Vojtesek, B, Hernychova, L, Walkinshaw, MD, Westwood, NJ & Hupp, TR 2015, 'Discovery of a novel ligand that modulates the protein-protein interactions of the AAA+ superfamily oncoprotein reptin', Chemical Science, vol. 6, no. 5, pp. 3109-3116. https://doi.org/10.1039/c4sc03885a
    Healy, Alan ; Houston, Douglas R. ; Remnant, Lucy ; Huart, Anne Sophie ; Brychtova, Veronika ; Maslon, Magda M. ; Meers, Olivia ; Muller, Petr ; Krejci, Adam ; Blackburn, Elizabeth A. ; Vojtesek, Borek ; Hernychova, Lenka ; Walkinshaw, Malcolm D. ; Westwood, Nicholas J. ; Hupp, Ted R. / Discovery of a novel ligand that modulates the protein-protein interactions of the AAA+ superfamily oncoprotein reptin. In: Chemical Science. 2015 ; Vol. 6, No. 5. pp. 3109-3116.
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