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A non-catalytic herpesviral protein reconfigures ERK-RSK signaling by targeting kinase docking systems in the host

Author

Listed:
  • Anita Alexa

    (Biomolecular Interactions Research Group, Institute of Organic Chemistry, Research Center for Natural Sciences)

  • Péter Sok

    (Biomolecular Interactions Research Group, Institute of Organic Chemistry, Research Center for Natural Sciences)

  • Fridolin Gross

    (IFOM, Istituto FIRC di Oncologia Molecolare)

  • Krisztián Albert

    (Biomolecular Interactions Research Group, Institute of Organic Chemistry, Research Center for Natural Sciences)

  • Evan Kobori

    (University of California San Diego)

  • Ádám L. Póti

    (Biomolecular Interactions Research Group, Institute of Organic Chemistry, Research Center for Natural Sciences)

  • Gergő Gógl

    (Biomolecular Interactions Research Group, Institute of Organic Chemistry, Research Center for Natural Sciences)

  • Isabel Bento

    (European Molecular Biology Laboratory)

  • Ersheng Kuang

    (Florida State University)

  • Susan S. Taylor

    (University of California San Diego)

  • Fanxiu Zhu

    (Florida State University)

  • Andrea Ciliberto

    (IFOM, Istituto FIRC di Oncologia Molecolare)

  • Attila Reményi

    (Biomolecular Interactions Research Group, Institute of Organic Chemistry, Research Center for Natural Sciences)

Abstract

The Kaposi’s sarcoma associated herpesvirus protein ORF45 binds the extracellular signal-regulated kinase (ERK) and the p90 Ribosomal S6 kinase (RSK). ORF45 was shown to be a kinase activator in cells but a kinase inhibitor in vitro, and its effects on the ERK-RSK complex are unknown. Here, we demonstrate that ORF45 binds ERK and RSK using optimized linear binding motifs. The crystal structure of the ORF45-ERK2 complex shows how kinase docking motifs recognize the activated form of ERK. The crystal structure of the ORF45-RSK2 complex reveals an AGC kinase docking system, for which we provide evidence that it is functional in the host. We find that ORF45 manipulates ERK-RSK signaling by favoring the formation of a complex, in which activated kinases are better protected from phosphatases and docking motif-independent RSK substrate phosphorylation is selectively up-regulated. As such, our data suggest that ORF45 interferes with the natural design of kinase docking systems in the host.

Suggested Citation

  • Anita Alexa & Péter Sok & Fridolin Gross & Krisztián Albert & Evan Kobori & Ádám L. Póti & Gergő Gógl & Isabel Bento & Ersheng Kuang & Susan S. Taylor & Fanxiu Zhu & Andrea Ciliberto & Attila Reményi, 2022. "A non-catalytic herpesviral protein reconfigures ERK-RSK signaling by targeting kinase docking systems in the host," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-28109-x
    DOI: 10.1038/s41467-022-28109-x
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