ArticleProtein science : a publication of the Protein Society2009
A chimeric mechanism for polyvalent trans-phosphorylation of PKA by PDK1.
Article in Protein science : a publication of the Protein Society, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed, 38 citations in OpenAlex.
- Mechanistic and evolutionary insights into isoform-specific 'supercharging' in DCLK family kinases.eLife · 2023Article
- An essentialFrontiers in parasitology · 2023Article
- The Tails of Protein Kinase A.Molecular pharmacology · 2022Review
- Utilizing a Baculovirus/Insect Cell Expression System and Expressed Protein Ligation (EPL) for Protein Semisynthesis.Current protocols · 2022Article
- mTORC2 controls the activity of PKC and Akt by phosphorylating a conserved TOR interaction motif.Science signaling · 2021Article
- Evolution of a dynamic molecular switch.IUBMB life · 2019Review
- Article
- Decoding the Interactions Regulating the Active State Mechanics of Eukaryotic Protein Kinases.PLoS biology · 2016Article
- Discovery of Allostery in PKA Signaling.Biophysical reviews · 2015Article
- Isoform-specific interactions between meprin metalloproteases and the catalytic subunit of protein kinase A: significance in acute and chronic kidney injury.American journal of physiology. Renal physiology · 2015Article
- Dynamic architecture of a protein kinase.Proceedings of the National Academy of Sciences of the United States of America · 2014Article
- Deciphering the structural basis of eukaryotic protein kinase regulation.PLoS biology · 2013Article
- Influence of N-myristylation and ligand binding on the flexibility of the catalytic subunit of protein kinase A.Biochemistry · 2013Article
- PKA: lessons learned after twenty years.Biochimica et biophysica acta · 2013Review
- Syk inhibits the activity of protein kinase A by phosphorylating tyrosine 330 of the catalytic subunit.The Journal of biological chemistry · 2013Article
- Assembly of allosteric macromolecular switches: lessons from PKA.Nature reviews. Molecular cell biology · 2012Review
- Design principles underpinning the regulatory diversity of protein kinases.Philosophical transactions of the Royal Society of London. Series B, Biological sciences · 2012Review
- Exploring the Plasmodium falciparum cyclic-adenosine monophosphate (cAMP)-dependent protein kinase (PfPKA) as a therapeutic target.Microbes and infection · 2012Review
- Cotranslational cis-phosphorylation of the COOH-terminal tail is a key priming step in the maturation of cAMP-dependent protein kinase.Proceedings of the National Academy of Sciences of the United States of America · 2012Article
- Direct modulation of the protein kinase A catalytic subunit α by growth factor receptor tyrosine kinases.Journal of cellular biochemistry · 2012Article
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
Abstract
Phosphorylation on the activation loop of AGC kinases is typically mediated by PDK1. The precise mechanism for this in-trans phosphorylation is unknown; however, docking of a hydrophobic (HF) motif in the C-tail of the substrate kinase onto the N-lobe of PDK1 is likely an essential step. Using a peptide array of PKA to identify other PDK1-interacting sites, we discovered a second AGC-conserved motif in the C-tail that interacts with PDK1. Since this motif [FD(X)(1-2)Y/F] lies in the active site tether region and in PKA contributes to ATP binding, we call it the Adenosine binding (Ade) motif. The Ade motif is conserved as a PDK1-interacting site in Akt and PRK2, and we predict it will be a PDK1-interacting site for most AGC kinases. In PKA, the HF motif is only recognized when the turn motif Ser338 is phosphorylated, possibly serving as a phosphorylation "switch" that regulates how the Ade and HF motifs interact with PDK1. These results demonstrate that the extended AGC C-tail serves as a polyvalent element that trans-regulates PDK1 for catalysis. Modeling of the PKA C-tail onto PDK1 structure creates two chimeric sites; the ATP binding pocket, which is completed by the Ade motif, and the C-helix, which is positioned by the HF motif. Together, they demonstrate substrate-assisted catalysis involving two kinases that have co-evolved as symbiotic partners. The highly regulated turn motifs are the most variable part of the AGC C-tail. Elucidating the highly regulated cis and trans functions of the AGC tail is a significant future challenge.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.