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A non-catalytic herpesviral protein reconfigures ERK-RSK signaling by targeting kinase docking systems in the host.
- Source :
-
Nature communications [Nat Commun] 2022 Jan 25; Vol. 13 (1), pp. 472. Date of Electronic Publication: 2022 Jan 25. - Publication Year :
- 2022
-
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.<br /> (© 2022. The Author(s).)
- Subjects :
- Cell Line
Computational Biology
Herpesvirus 8, Human chemistry
Herpesvirus 8, Human isolation & purification
Humans
Immediate-Early Proteins chemistry
Mitogen-Activated Protein Kinase 1 metabolism
Phosphorylation
Ribosomal Protein S6 Kinases, 90-kDa metabolism
Sarcoma, Kaposi pathology
Sarcoma, Kaposi virology
Signal Transduction
Crystallography, X-Ray methods
Herpesvirus 8, Human metabolism
Immediate-Early Proteins metabolism
Mitogen-Activated Protein Kinase 1 chemistry
Ribosomal Protein S6 Kinases, 90-kDa chemistry
Sarcoma, Kaposi metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 2041-1723
- Volume :
- 13
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Nature communications
- Publication Type :
- Academic Journal
- Accession number :
- 35078976
- Full Text :
- https://doi.org/10.1038/s41467-022-28109-x