Figure 4.

Regulatory rearrangements in Cbl proteins. (a) ‘Closed’ conformation of Cbl based on the crystal structure of the apo c-Cbl amino-terminal region, comprising the tyrosine kinase binding module, the helical linker region, and the RING domain [PDB: 2Y1M] [29]. The regulatory tyrosine, Y371, located in the helical linker region, is buried in a hydrophobic core formed by the SH2 domain and the four-helix bundle in the tyrosine kinase binding module. (b) ‘Partially open’ conformation of Cbl based on the co-crystal structure of c-Cbl amino-terminal region with a ZAP70-derived phosphopeptide and the E2 enzyme UbcH7 [PDB: 1FBV] [91]. Phosphopeptide binding induces a shift in the SH2 domain that perturbs the interface between the helical linker and the tyrosine kinase binding module, probably favoring dissociation of the RING domain from the tyrosine kinase binding module and thus increasing the accessibility of the E2 binding surface. (c) ‘Open’ conformation of Cbl based on the co-crystal structure of phosphorylated c-Cbl bound to a ZAP7-derived phosphopeptide and UbcH5B [PDB: 4A4C] [29]. The phosphorylated regulatory tyrosine, Tyr371, interacts with residues in the E2 binding surface of the RING domain. The RING domain is situated on the opposite side of the tyrosine kinase binding module compared to (b).

Lorenz et al. BMC Biology 2013 11:65   doi:10.1186/1741-7007-11-65
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