Polycation-π interactions are a driving force for molecular recognition by an intrinsically disordered oncoprotein family.

TitlePolycation-π interactions are a driving force for molecular recognition by an intrinsically disordered oncoprotein family.
Publication TypeJournal Article
Year of Publication2013
AuthorsSong, J., Ng S. Chun, Tompa P., Lee K. A. W., and Chan H. Sun
JournalPLoS Comput Biol
Volume9
Issue9
Paginatione1003239
Date Published2013
ISSN1553-7358
KeywordsIntrinsically Disordered Proteins, Models, Chemical, Oncogene Proteins, Polyamines, Sarcoma, Ewing
Abstract

Molecular recognition by intrinsically disordered proteins (IDPs) commonly involves specific localized contacts and target-induced disorder to order transitions. However, some IDPs remain disordered in the bound state, a phenomenon coined "fuzziness", often characterized by IDP polyvalency, sequence-insensitivity and a dynamic ensemble of disordered bound-state conformations. Besides the above general features, specific biophysical models for fuzzy interactions are mostly lacking. The transcriptional activation domain of the Ewing's Sarcoma oncoprotein family (EAD) is an IDP that exhibits many features of fuzziness, with multiple EAD aromatic side chains driving molecular recognition. Considering the prevalent role of cation-π interactions at various protein-protein interfaces, we hypothesized that EAD-target binding involves polycation- π contacts between a disordered EAD and basic residues on the target. Herein we evaluated the polycation-π hypothesis via functional and theoretical interrogation of EAD variants. The experimental effects of a range of EAD sequence variations, including aromatic number, aromatic density and charge perturbations, all support the cation-π model. Moreover, the activity trends observed are well captured by a coarse-grained EAD chain model and a corresponding analytical model based on interaction between EAD aromatics and surface cations of a generic globular target. EAD-target binding, in the context of pathological Ewing's Sarcoma oncoproteins, is thus seen to be driven by a balance between EAD conformational entropy and favorable EAD-target cation-π contacts. Such a highly versatile mode of molecular recognition offers a general conceptual framework for promiscuous target recognition by polyvalent IDPs.

DOI10.1371/journal.pcbi.1003239
Alternate JournalPLoS Comput. Biol.
PubMed ID24086122
PubMed Central IDPMC3784488
Grant ListMOP-84281 / / Canadian Institutes of Health Research / Canada
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