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research article

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

Reckel, Sina
•
Gehin, Charlotte
•
Tardivon, Delphine
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2017
Nature Communications

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.

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Type
research article
DOI
10.1038/s41467-017-02313-6
Web of Science ID

WOS:000417884500007

Author(s)
Reckel, Sina
Gehin, Charlotte
Tardivon, Delphine
Georgeon, Sandrine
Kukenshoner, Tim
Loehr, Frank
Koide, Akiko
Buchner, Lena
Panjkovich, Alejandro
Reynaud, Aline
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Date Issued

2017

Publisher

Springer Nature

Published in
Nature Communications
Volume

8

Issue

1

Article Number

2101

Note

This article is licensed under a Creative Commons Attribution 4.0 International License

Editorial or Peer reviewed

REVIEWED

Written at

EPFL

EPFL units
UPHAN  
Available on Infoscience
January 15, 2018
Use this identifier to reference this record
https://infoscience.epfl.ch/handle/20.500.14299/144035
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