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

Author

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  • Sina Reckel

    (School of Life Sciences, École polytechnique fédérale de Lausanne (EPFL))

  • Charlotte Gehin

    (European Molecular Biology Laboratory (EMBL))

  • Delphine Tardivon

    (School of Life Sciences, École polytechnique fédérale de Lausanne (EPFL))

  • Sandrine Georgeon

    (School of Life Sciences, École polytechnique fédérale de Lausanne (EPFL))

  • Tim Kükenshöner

    (School of Life Sciences, École polytechnique fédérale de Lausanne (EPFL))

  • Frank Löhr

    (Goethe University Frankfurt)

  • Akiko Koide

    (New York University Langone Medical Center
    New York University School of Medicine
    New York University School of Medicine)

  • Lena Buchner

    (Goethe University Frankfurt)

  • Alejandro Panjkovich

    (Hamburg Outstation)

  • Aline Reynaud

    (School of Life Sciences, École polytechnique fédérale de Lausanne (EPFL))

  • Sara Pinho

    (School of Life Sciences, École polytechnique fédérale de Lausanne (EPFL))

  • Barbara Gerig

    (School of Life Sciences, École polytechnique fédérale de Lausanne (EPFL))

  • Dmitri Svergun

    (Hamburg Outstation)

  • Florence Pojer

    (School of Life Sciences, École polytechnique fédérale de Lausanne (EPFL))

  • Peter Güntert

    (Goethe University Frankfurt
    Laboratory of Physical Chemistry, ETH Zürich
    Graduate School of Science, Tokyo Metropolitan University)

  • Volker Dötsch

    (Goethe University Frankfurt)

  • Shohei Koide

    (New York University Langone Medical Center
    New York University School of Medicine
    New York University School of Medicine)

  • Anne-Claude Gavin

    (European Molecular Biology Laboratory (EMBL))

  • Oliver Hantschel

    (School of Life Sciences, École polytechnique fédérale de Lausanne (EPFL))

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.

Suggested Citation

  • Sina Reckel & Charlotte Gehin & Delphine Tardivon & Sandrine Georgeon & Tim Kükenshöner & Frank Löhr & Akiko Koide & Lena Buchner & Alejandro Panjkovich & Aline Reynaud & Sara Pinho & Barbara Gerig & , 2017. "Structural and functional dissection of the DH and PH domains of oncogenic Bcr-Abl tyrosine kinase," Nature Communications, Nature, vol. 8(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_s41467-017-02313-6
    DOI: 10.1038/s41467-017-02313-6
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