Publication details
Discovery of a novel ligand that modulates the protein-protein interactions of the AAA plus superfamily oncoprotein reptin
| Authors | |
|---|---|
| Year of publication | 2015 |
| Type | Article in Periodical |
| Magazine / Source | CHEMICAL SCIENCE |
| Citation | |
| Web | http://dx.doi.org/10.1039/c4sc03885a |
| Doi | http://dx.doi.org/10.1039/c4sc03885a |
| Description | 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. |