2OO9

crystal structure of the UBA domain from human c-Cbl ubiquitin ligase

Summary for 2OO9

• Entry DOI: 10.2210/pdb2oo9/pdb
• Related: 2OOA 2OOB
• Descriptor: E3 ubiquitin-protein ligase CBL (2 entities in total)
• Functional Keywords: alpha-helical domain, homodimer, ligase
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: P22681
• Total number of polymer chains: 3
• Total formula weight: 15517.37

Authors

Kozlov, G.,Gehring, K. (deposition date: 2007-01-25, release date: 2007-02-06, Last modification date: 2024-10-30)

Primary citation

Kozlov, G.,Peschard, P.,Zimmerman, B.,Lin, T.,Moldoveanu, T.,Mansur-Azzam, N.,Gehring, K.,Park, M.
Structural basis for UBA-mediated dimerization of c-Cbl ubiquitin ligase.
J.Biol.Chem., 282:27547-27555, 2007

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.

PubMed: 17635922
DOI: 10.1074/jbc.M703333200

Experimental method

X-RAY DIFFRACTION (2.1 Å)