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

Nat Commun. 2022 Jan 25;13(1):472. doi: 10.1038/s41467-022-28109-x.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line
  • Computational Biology
  • Crystallography, X-Ray / methods*
  • Herpesvirus 8, Human / chemistry
  • Herpesvirus 8, Human / isolation & purification
  • Herpesvirus 8, Human / metabolism*
  • Humans
  • Immediate-Early Proteins / chemistry
  • Immediate-Early Proteins / metabolism*
  • Mitogen-Activated Protein Kinase 1 / chemistry*
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Phosphorylation
  • Ribosomal Protein S6 Kinases, 90-kDa / chemistry*
  • Ribosomal Protein S6 Kinases, 90-kDa / metabolism
  • Sarcoma, Kaposi / metabolism*
  • Sarcoma, Kaposi / pathology
  • Sarcoma, Kaposi / virology
  • Signal Transduction

Substances

  • Immediate-Early Proteins
  • ORF45 protein, Kaposi's sarcoma-associated herpesvirus
  • RPS6KA4 protein, human
  • Ribosomal Protein S6 Kinases, 90-kDa
  • MAPK1 protein, human
  • Mitogen-Activated Protein Kinase 1