Structural and functional dissection of the DH and PH domains of oncogenic Bcr-Abl tyrosine kinase

Nat Commun. 2017 Dec 13;8(1):2101. doi: 10.1038/s41467-017-02313-6.


The two isoforms of the Bcr-Abl tyrosine kinase, p210 and p190, are associated with different leukemias and have a dramatically different signaling network, despite similar kinase activity. To provide a molecular rationale for these observations, we study the Dbl-homology (DH) and Pleckstrin-homology (PH) domains of Bcr-Abl p210, which constitute the only structural differences to p190. Here we report high-resolution structures of the DH and PH domains and characterize conformations of the DH-PH unit in solution. Our structural and functional analyses show no evidence that the DH domain acts as a guanine nucleotide exchange factor, whereas the PH domain binds to various phosphatidylinositol-phosphates. PH-domain mutants alter subcellular localization and result in decreased interactions with p210-selective interaction partners. Hence, the PH domain, but not the DH domain, plays an important role in the formation of the differential p210 and p190 Bcr-Abl signaling networks.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carcinogenesis
  • Crystallography, X-Ray
  • Fusion Proteins, bcr-abl / chemistry*
  • Fusion Proteins, bcr-abl / genetics
  • Fusion Proteins, bcr-abl / metabolism
  • Humans
  • Leukemia / genetics
  • Leukemia / metabolism
  • Magnetic Resonance Spectroscopy
  • Models, Molecular*
  • Pleckstrin Homology Domains*
  • Protein Domains*
  • Scattering, Small Angle
  • Signal Transduction
  • X-Ray Diffraction


  • Fusion Proteins, bcr-abl