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

Nature Chemical Biology volume 8, pages 590–596 (2012)Cite this article

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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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Figure 1: Structural and dynamic properties of CrkL.
Figure 2: Binding of pTyr- and PPII-peptide ligands to CrkL and CrkII.
Figure 3: Structural and dynamic properties of pCrkL.
Figure 4: Effect of Tyr207 phosphorylation on CrkL folding and its association with Abl kinase.
Figure 5: CrkL versus CrkII in integrin signaling.

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Acknowledgements

We thank S. Karamanou for performing the MALLS experiments and D. Duffield for collecting the mass spectrometry data. This work was supported by the US Department of Defense (R.B.B.) and the US National Institutes of Health (GM80308 to C.G.K.).

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Author notes

  1. Wojciech Jankowski and Tamjeed Saleh: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, New Jersey, USA

    Wojciech Jankowski, Tamjeed Saleh, Ming-Tao Pai & Charalampos G Kalodimos

  2. Department of Biochemistry and Molecular Biology, New Jersey Medical School, University of Medicine and Dentistry of New Jersey, Newark, New Jersey, USA

    Ganapathy Sriram & Raymond B Birge

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  1. Wojciech Jankowski
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Contributions

W.J., T.S., G.S., R.B.B. and C.G.K. designed research; W.J., T.S., M.-T.P. and G.S. performed research; W.J., T.S., M.-T.P., G.S., R.B.B. and C.G.K. analyzed data; W.J., T.S. and C.G.K. wrote the manuscript.

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Correspondence to Charalampos G Kalodimos.

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Jankowski, W., Saleh, T., Pai, MT. et al. Domain organization differences explain Bcr-Abl's preference for CrkL over CrkII. Nat Chem Biol 8, 590–596 (2012). https://doi.org/10.1038/nchembio.954

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