

Other version: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5727386/
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Structural and functional dissection of the DH and PH domains of oncogenic Bcr-Abl tyrosine kinase |
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Authors | ![]() | |
Published in | Nature communications. 2017, vol. 8, no. 1, 2101 | |
Abstract | 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. | |
Keywords | 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 | |
Identifiers | PMID: 29235475 | |
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![]() ![]() Other version: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5727386/ |
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Research groups | Métabolisme des lipides (1001) NCCR Chemical Biology | |
Projects | Swiss National Science Foundation: 31003A_140913 Autre: ERC-2016-CoG 682311-ONCOINTRABODY | |
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 https://archive-ouverte.unige.ch/unige:124440 |