Download MendeleyStructural basis for UBA-mediated dimerization of c-Cbl ubiquitin ligase.
Kozlov, G., Peschard, P., Zimmerman, B., Lin, T., Moldoveanu, T., Mansur-Azzam, N., Gehring, K., Park, M.(2007) J Biol Chem 282: 27547-27555
- PubMed: 17635922
- DOI: https://doi.org/10.1074/jbc.M703333200
- Primary Citation of Related Structures:
2OO9 - PubMed Abstract:
Ligand-induced down-regulation by the ubiquitin-protein ligases, c-Cbl and Cbl-b, controls signaling downstream from many receptor-tyrosine kinases (RTK). Cbl proteins bind to phosphotyrosine residues on activated RTKs to affect ligand-dependent ubiquitylation of these receptors targeting them for degradation in the lysosome. Both c-Cbl and Cbl-b contain a ubiquitin-associated (UBA) domain, which is important for Cbl dimerization and tyrosine phosphorylation; however, the mechanism of UBA-mediated dimerization and its requirement for Cbl biological activity is unclear. Here, we report the crystal structure of the UBA domain of c-Cbl refined to 2.1-A resolution. The structure reveals the protein is a symmetric dimer tightly packed along a large hydrophobic surface formed by helices 2 and 3. NMR chemical shift mapping reveals heterodimerization can occur with the related Cbl-b UBA domain via the same surface employed for homodimerization. Disruption of c-Cbl dimerization by site-directed mutagenesis impairs c-Cbl phosphorylation following activation of the Met/hepatocyte growth factor RTK and c-Cbl-dependent ubiquitination of Met. This provides direct evidence for a role of Cbl dimerization in terminating signaling following activation of RTKs.
Organizational Affiliation:
Department of Biochemistry, McGill University.
