ArticleScientific reports2020
Activation of RSK by phosphomimetic substitution in the activation loop is prevented by structural constraints.
Article in Scientific reports, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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22 citing papers in PubMed, 28 citations in OpenAlex.
- Accessing intractable, phosphorylated intrinsically disordered proteins via a protease-cleavable inclusion body tag.Protein science : a publication of the Protein Society · 2026Article
- Article
- SF3B1 Phosphorylation Prompts U2AF2 Dissociation for Widespread Control of pre-mRNA Splicing.bioRxiv : the preprint server for biology · 2026Article
- Dissecting the Mechanisms Underlying Substrate Recognition and Functional Regulation of O-GlcNAc Cycling Enzymes.ACS chemical biology · 2025Review
- RiSKs in Computational Modeling of Isoform-Selective RSK Inhibitors.Journal of chemical information and modeling · 2025Review
- Unraveling the Mystery of Insulin Resistance: From Principle Mechanistic Insights and Consequences to Therapeutic Interventions.International journal of molecular sciences · 2025Review
- Phosphate-dependent nuclear export via a non-classical NES class recognized by exportin Msn5.Nature communications · 2025Article
- Ribosomal s6 kinase is a mediator of aquaporin-2 S256 phosphorylation and membrane accumulation after EGFR inhibition with erlotinib.American journal of physiology. Renal physiology · 2025Article
- Site-specifically Phosphorylated Hsp90C-terminal Domain Variants Provide Access to Deciphering the Chaperone Code.Chemistry (Weinheim an der Bergstrasse, Germany) · 2025Article
- Phosphorylation of disordered proteins tunes local and global intramolecular interactions.Biophysical journal · 2024Article
- Serum/glucocorticoid regulated kinase 1 (SGK1) in neurological disorders: pain or gain.Experimental neurology · 2024Review
- GpsB Coordinates StkP Signaling as a PASTA Kinase Adaptor in Streptococcus pneumoniae Cell Division.Journal of molecular biology · 2024Article
- Structural and functional effects of phosphopriming and scaffolding in the kinase GSK-3β.Science signaling · 2024Article
- Phosphorylation of disordered proteins tunes local and global intramolecular interactions.bioRxiv : the preprint server for biology · 2024Article
- Genetic Encoding of Phosphorylated Amino Acids into Proteins.Chemical reviews · 2024Review
- Activation and inhibition of the C-terminal kinase domain of p90 ribosomal S6 kinases.Life science alliance · 2023Article
- An essentialFrontiers in parasitology · 2023Article
- A specific type of Argonaute phosphorylation regulates binding to microRNAs during C. elegans development.Cell reports · 2022Article
- Accessing isotopically labeled proteins containing genetically encoded phosphoserine for NMR with optimized expression conditions.The Journal of biological chemistry · 2022Article
- Phosphorylated and Phosphomimicking Variants May Differ-A Case Study of 14-3-3 Protein.Frontiers in chemistry · 2022Article
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Authors and funding
11 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The activation of the majority of AGC kinases is regulated by two phosphorylation events on two conserved serine/threonine residues located on the activation loop and on the hydrophobic motif, respectively. In AGC kinase family, phosphomimetic substitutions with aspartate or glutamate, leading to constitutive activation, have frequently occurred at the hydrophobic motif site. On the contrary, phosphomimetic substitutions in the activation loop are absent across the evolution of AGC kinases. This observation is explained by the failure of aspartate and glutamate to mimic phosphorylatable serine/threonine in this regulatory site. By detailed 3D structural simulations of RSK2 and further biochemical evaluation in cells, we show that the phosphomimetic residue on the activation loop fails to form a critical salt bridge with R114, necessary to reorient the αC-helix and to activate the protein. By a phylogenetic analysis, we point at a possible coevolution of a phosphorylatable activation loop and the presence of a conserved positively charged amino acid on the αC-helix. In sum, our analysis leads to the unfeasibility of phosphomimetic substitution in the activation loop of RSK and, at the same time, highlights the peculiar structural role of activation loop phosphorylation.
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