Distinct ubiquitin binding modes exhibited by SH3 domains: molecular determinants and functional implications
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AutorOrtega-Roldán, José Luis; Casares Atienza, Salvador; Ringkjøbing Jensen, Malene; Cárdenes, Nayra; Bravo, Jerónimo; Blackledge, Martin; Azuaga Fortes, Ana Isabel; Nuland, Nico A. J. van
Public Library of Science (PLOS)
Binding analysisCrystal structureCrystal structure refinementNuclear magnetic resonancePhenylalanineProtein interactionsTyrosineUbiquitination
Ortega Roldán, J.L.; et al. Distinct ubiquitin binding modes exhibited by SH3 domains: molecular determinants and functional implications. Plos One, 8(9): e73018 (2013). [http://hdl.handle.net/10481/29706]
PatrocinadorThis research was funded by grant BIO2005-04650 from the Spanish Ministry of Education and Science (MEC) and FQM-02838 from the Andalucia Regional Government.
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.