Structural basis for ubiquitin-mediated dimerization and activation of the ubiquitin protein ligase Cbl-b.
Cbl proteins are E3 ubiquitin ligases that are negative regulators of many receptor tyrosine kinases. Cbl-b and c-Cbl contain a ubiquitin-associated (UBA) domain, which is present in a variety of proteins involved in ubiquitin-mediated processes. Despite high sequence identity, Cbl UBA domains display remarkably different ubiquitin-binding properties. Here, we report ... the crystal structure of the UBA domain of Cbl-b in complex with ubiquitin at 1.9 A resolution. The structure reveals an atypical mechanism of ubiquitin recognition by the first helix of the UBA. Helices 2 and 3 of the UBA domain form a second binding surface, which mediates UBA dimerization in the crystal and in solution. Site-directed mutagenesis demonstrates that Cbl-b dimerization is regulated by ubiquitin binding and required for tyrosine phosphorylation of Cbl-b and ubiquitination of Cbl-b substrates. These studies demonstrate a role for ubiquitin in regulating biological activity by promoting protein dimerization.
Mesh Terms:
Adaptor Proteins, Signal Transducing, Amino Acid Sequence, Binding Sites, Cell Line, Crystallization, Dimerization, Enzyme Activation, Hela Cells, Humans, Immunoblotting, Immunoprecipitation, Kidney, Molecular Sequence Data, Mutagenesis, Site-Directed, Protein Conformation, Proto-Oncogene Proteins c-cbl, Sequence Homology, Amino Acid, Transfection, Ubiquitin
Adaptor Proteins, Signal Transducing, Amino Acid Sequence, Binding Sites, Cell Line, Crystallization, Dimerization, Enzyme Activation, Hela Cells, Humans, Immunoblotting, Immunoprecipitation, Kidney, Molecular Sequence Data, Mutagenesis, Site-Directed, Protein Conformation, Proto-Oncogene Proteins c-cbl, Sequence Homology, Amino Acid, Transfection, Ubiquitin
Mol. Cell
Date: Aug. 03, 2007
PubMed ID: 17679095
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