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

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 and Attila Reményi ()
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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

Nature Communications, 2022, vol. 13, issue 1, 1-19

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-28109-x

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