title: Domain organization differences explain Bcr-Abl's preference for CrkL over CrkII.
abstract: 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 markedly different than the corresponding structures of CrkII. As a result, the binding activities of the Src homology 2 and Src homology 3 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.
authors.affiliation: Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, New Jersey, USA.
authors.forename: Wojciech
authors.initials: W
authors.lastname: Jankowski
authors.forename: Tamjeed
authors.initials: T
authors.lastname: Saleh
authors.forename: Ming-Tao
authors.initials: MT
authors.lastname: Pai
authors.forename: Ganapathy
authors.initials: G
authors.lastname: Sriram
authors.forename: Raymond B
authors.initials: RB
authors.lastname: Birge
authors.forename: Charalampos G
authors.initials: CG
authors.lastname: Kalodimos
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D001665:Binding Sites; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D019906:Nuclear Magnetic Resonance, Biomolecular; D009687:Nuclear Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D050737:Proto-Oncogene Proteins c-crk / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D018909:src Homology Domains
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C082869:CRKL protein; D009687:Nuclear Proteins; D050737:Proto-Oncogene Proteins c-crk; D016044:Fusion Proteins, bcr-abl