Scientific article
Open access

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

Published inNature Communications, vol. 8, no. 1, 2101
Publication date2017

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.

  • Carcinogenesis
  • Crystallography
  • X-Ray
  • Fusion Proteins
  • Bcr-abl/chemistry/genetics/metabolism
  • Humans
  • Leukemia/genetics/metabolism
  • Magnetic Resonance Spectroscopy
  • Models
  • Molecular
  • Pleckstrin Homology Domains
  • Protein Domains
  • Scattering
  • Small Angle
  • Signal Transduction
  • X-Ray Diffraction
Affiliation Not a UNIGE publication
Citation (ISO format)
RECKEL, Sina et al. Structural and functional dissection of the DH and PH domains of oncogenic Bcr-Abl tyrosine kinase. In: Nature Communications, 2017, vol. 8, n° 1, p. 2101. doi: 10.1038/s41467-017-02313-6
Main files (1)
Article (Published version)
ISSN of the journal2041-1723

Technical informations

Creation10/14/2019 1:06:00 PM
First validation10/14/2019 1:06:00 PM
Update time03/15/2023 6:11:01 PM
Status update03/15/2023 6:10:59 PM
Last indexation02/12/2024 11:43:49 AM
All rights reserved by Archive ouverte UNIGE and the University of GenevaunigeBlack