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, Attila Reményi

Nature communications 2022 Jan 25

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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. © 2022. The Author(s).

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. A non-catalytic herpesviral protein reconfigures ERK-RSK signaling by targeting kinase docking systems in the host. Nature communications. 2022 Jan 25;13(1):472