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


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.

SUBMITTER: Ortega Roldan JL 

PROVIDER: S-EPMC3770644 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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

Ortega Roldan Jose L JL   Casares Salvador S   Ringkjøbing Jensen Malene M   Cárdenes Nayra N   Bravo Jerónimo J   Blackledge Martin M   Azuaga Ana I AI   van Nuland Nico A J NA  

PloS one 20130911 9


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 ubiqui  ...[more]

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