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

Sina Reckel, Charlotte Gehin, Delphine Tardivon, Sandrine Georgeon, Tim Kükenshöner, Frank Löhr, Akiko Koide, Lena Buchner, Alejandro Panjkovich, Aline Reynaud, Sara Pinho, Barbara Gerig, Dmitri Svergun, Florence Pojer, Peter Güntert, Volker Dötsch, Shohei Koide, Anne-Claude Gavin and Oliver Hantschel ()
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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
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
Volker Dötsch: Goethe University Frankfurt
Shohei Koide: New York University Langone Medical Center
Anne-Claude Gavin: European Molecular Biology Laboratory (EMBL)
Oliver Hantschel: School of Life Sciences, École polytechnique fédérale de Lausanne (EPFL)

Nature Communications, 2017, vol. 8, issue 1, 1-14

Abstract: 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.

Date: 2017
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_s41467-017-02313-6

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DOI: 10.1038/s41467-017-02313-6

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