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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 590-596 |
| Number of pages | 7 |
| Journal | Nature Chemical Biology |
| Volume | 8 |
| Issue number | 6 |
| DOIs | |
| State | Published - Jun 2012 |
| Externally published | Yes |
Bibliographical note
Funding Information: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.).