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

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

Author information

1
Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, École polytechnique fédérale de Lausanne (EPFL), 1015, Lausanne, Switzerland.
2
Structural and Computational Biology Unit, European Molecular Biology Laboratory (EMBL), 69117, Heidelberg, Germany.
3
Institute of Biophysical Chemistry, Goethe University Frankfurt, 60438, Frankfurt, Germany.
4
Laura and Isaac Perlmutter Cancer Center, New York University Langone Medical Center, New York, NY, 10016, USA.
5
Department of Medicine, New York University School of Medicine, New York, NY, 10016, USA.
6
Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY, 10016, USA.
7
European Molecular Biology Laboratory (EMBL), Hamburg Outstation, 22607, Hamburg, Germany.
8
Protein Crystallography Core Facility, School of Life Sciences, École polytechnique fédérale de Lausanne (EPFL), 1015, Lausanne, Switzerland.
9
Laboratory of Physical Chemistry, ETH Zürich, 8093, Zürich, Switzerland.
10
Graduate School of Science, Tokyo Metropolitan University, Tokyo, 192-0397, Japan.
11
Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, École polytechnique fédérale de Lausanne (EPFL), 1015, Lausanne, Switzerland. oliver.hantschel@epfl.ch.

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.

PMID:
29235475
PMCID:
PMC5727386
DOI:
10.1038/s41467-017-02313-6
[Indexed for MEDLINE]
Free PMC Article

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