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

Nature Chemical Biology
Wojciech JankowskiCharalampos G Kalodimos

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.

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Methods Mentioned

BETA
light scattering
NMR
isothermal titration calorimetry
gel filtration
pull-down
nucleotide exchange
GTPases
gel

Software Mentioned

TALOS

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