DOC_RSK_DDVF_1

The 90 kDa ribosomal S6 kinases (RSK) are highly conserved Ser/Thr kinases, which are downstream effectors of the Ras–extracellular signal-regulated kinase (ERK) and mitogen-activated protein kinase (MAPK) signaling cascade. Unusually, RSKs have two protein kinase phosphorylation domains. The human RSK family consists of four isoforms (RSK1–4) and regulates diverse cellular processes, such as cell growth, cell survival, and proliferation. In addition, the members of the RSK family phosphorylate translational regulators, including the eukaryotic initiation factor 4B (EIF4B, P23588), the 40S ribosomal protein S6 (RPS6, P62753), and the tumor suppressors Tuberin (TSC2, P49815) and Programmed cell death protein 4 (PDCD4, Q53EL6). There are accumulating data that SLiMs in pathogenic organisms often evolve to mimic and subvert functional host protein interfaces. Proteins from several unrelated viruses and bacteria, including the Theiler’s murine encephalomyelitis virus (TMEV) leader (L) protein, the PRF45 (Human herpesvirus 8), and the YopM of bacteria from the genus Yersinia, can recruit the cellular p90-ribosomal protein S6 kinases (RSKs) through a conserved DDVF motif located in an IDD region. The consequence of the protein-protein interactions is to maintain the RSK kinases in an active state and influence the phosphorylation of RSK downstream substrates (Sorgeloos,2022).
The molecular details of the interaction of the DDVF motif with the N-terminal kinase domain (NTKD) are more complex than is typical for Linear Motifs which mostly bind ordered surface pockets of the core folded domain. TMEV Leader Protein (L) (P13899), ORF45 (F5HDE4), and YopM (P17778) bind a conserved but surface-located loop located on the RSK N-terminal kinase domains, KAKLGM, as shown by cross-linking experiments, as well as crystallographic data of the RSK2 NTKD in complex with ORF45 (7OPO; Alexa,2022). While Val and Phe from ORF45 DDVF are deeply buried, the backbone atom of the following amino acid (after the Phe) and the Val from motif makes contact with the NTKD via β-augmentation. Interestingly, the β-strand which engages from the NTKD also forms additional contacts with the IDD region containing DDVF which is wrapped around the bulge on the kinase surface (formed by the mentioned β-strand on the NTKD). The long IDD region also helps dimerization of the kinase as it interacts with the N-terminal region of one RSK copy and C-terminus part of another RSK molecule (7OPO; Alexa,2022).
The L proteins from different TMEV virus strains (P08544 and P08545) have high sequence similarity to the canonical TMEV (P13899), and are likely to interact in a similar manner to the conserved loop of RSKs. The RSK KAKLGM motif is conserved in the N-terminal kinase domain (NTKD) of all human RSK isoforms and regulates RSK activity, likely acting as an allosteric regulation site.
The downstream consequences are various, e.g., YopM inhibits effector-triggered pyrin inflammasome activation (Ratner,2016), whereas, upon RSK recruitment and accumulation of c-Fos, ORF45 accelerates lytic replication of Kaposi's Sarcoma-Associated Herpesvirus (Li,2015). The RSK recruitment by cardiovirus L protein leads to the inhibition of the antiviral eukaryotic initiation factor 2 alpha kinase 2 (EIF2AK2) (Borghese,2019).