Distinct ubiquitin binding modes exhibited by SH3 domains: molecular determinants and functional implications.

TitleDistinct ubiquitin binding modes exhibited by SH3 domains: molecular determinants and functional implications.
Publication TypeJournal Article
Year of Publication2013
AuthorsRoldan, J. L. Ortega, S. Casares, M. Ringkjøbi Jensen, N. Cárdenes, J. Bravo, M. Blackledge, A. I. Azuaga, and N. A. J. van Nuland
JournalPLoS One
Volume8
Issue9
Paginatione73018
Date Published2013
ISSN1932-6203
KeywordsAdaptor Proteins, Signal Transducing, Cytoskeletal Proteins, Models, Molecular, Mutation, Nuclear Magnetic Resonance, Biomolecular, Protein Binding, Protein Conformation, Protein Interaction Domains and Motifs, src Homology Domains, Ubiquitin
Abstract

SH3 domains constitute a new type of ubiquitin-binding domains. We previously showed that the third SH3 domain (SH3-C) of CD2AP binds ubiquitin in an alternative orientation. We have determined the structure of the complex between first CD2AP SH3 domain and ubiquitin and performed a structural and mutational analysis to decipher the determinants of the SH3-C binding mode to ubiquitin. We found that the Phe-to-Tyr mutation in CD2AP and in the homologous CIN85 SH3-C domain does not abrogate ubiquitin binding, in contrast to previous hypothesis and our findings for the first two CD2AP SH3 domains. The similar alternative binding mode of the SH3-C domains of these related adaptor proteins is characterised by a higher affinity to C-terminal extended ubiquitin molecules. We conclude that CD2AP/CIN85 SH3-C domain interaction with ubiquitin constitutes a new ubiquitin-binding mode involved in a different cellular function and thus changes the previously established mechanism of EGF-dependent CD2AP/CIN85 mono-ubiquitination.

DOI10.1371/journal.pone.0073018
Alternate JournalPLoS ONE
PubMed ID24039852
PubMed Central IDPMC3770644
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