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The SH2 domain of Abl kinases regulates kinase autophosphorylation by controlling activation loop accessibility

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  • Allan Joaquim Lamontanara

    (Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, École polytechnique fédérale de Lausanne (EPFL))

  • Sandrine Georgeon

    (Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, École polytechnique fédérale de Lausanne (EPFL))

  • Giancarlo Tria

    (European Molecular Biology Laboratory, Hamburg Outstation)

  • Dmitri I. Svergun

    (European Molecular Biology Laboratory, Hamburg Outstation)

  • Oliver Hantschel

    (Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, École polytechnique fédérale de Lausanne (EPFL)
    ISREC Foundation Chair in Translational Oncology)

Abstract

The activity of protein kinases is regulated by multiple molecular mechanisms, and their disruption is a common driver of oncogenesis. A central and almost universal control element of protein kinase activity is the activation loop that utilizes both conformation and phosphorylation status to determine substrate access. In this study, we use recombinant Abl tyrosine kinases and conformation-specific kinase inhibitors to quantitatively analyse structural changes that occur after Abl activation. Allosteric SH2–kinase domain interactions were previously shown to be essential for the leukemogenesis caused by the Bcr–Abl oncoprotein. We find that these allosteric interactions switch the Abl activation loop from a closed to a fully open conformation. This enables the trans-autophosphorylation of the activation loop and requires prior phosphorylation of the SH2–kinase linker. Disruption of the SH2–kinase interaction abolishes activation loop phosphorylation. Our analysis provides a molecular mechanism for the SH2 domain-dependent activation of Abl that may also regulate other tyrosine kinases.

Suggested Citation

  • Allan Joaquim Lamontanara & Sandrine Georgeon & Giancarlo Tria & Dmitri I. Svergun & Oliver Hantschel, 2014. "The SH2 domain of Abl kinases regulates kinase autophosphorylation by controlling activation loop accessibility," Nature Communications, Nature, vol. 5(1), pages 1-11, December.
  • Handle: RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms6470
    DOI: 10.1038/ncomms6470
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    Cited by:

    1. Nina Schmidt & Amit Kumar & Lukas Korf & Adrian Valentin Dinh-Fricke & Frank Abendroth & Akiko Koide & Uwe Linne & Magdalena Rakwalska-Bange & Shohei Koide & Lars-Oliver Essen & Olalla Vázquez & Olive, 2024. "Development of mirror-image monobodies targeting the oncogenic BCR::ABL1 kinase," Nature Communications, Nature, vol. 15(1), pages 1-19, December.

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