Domain organization differences explain Bcr-Abl’s preference for CrkL over CrkII

CrkL is a key signaling protein that mediates the leukemogenic activity of Bcr-Abl. CrkL is thought to adopt a structure that is similar to that of its CrkII homolog. The two proteins share high sequence identity and indistinguishable ligand binding preferences; yet they have distinct physiological roles. Here we show that the structures of CrkL and phosphorylated CrkL are drastically different than the corresponding structures of CrkII. As a result, the binding activities of the SH2 and SH3 domains in the two proteins are regulated in a distinct manner and to a different extent. The different structural architecture of CrkL and CrkII may account for their distinct functional roles. The data show that CrkL forms a constitutive complex with Abl thus explaining the strong preference of Bcr-Abl for CrkL. The results also highlight how the structural organization of the modular domains in adaptor proteins can control signaling outcome.