ArticlePLoS biology2015
Single Turnover Autophosphorylation Cycle of the PKA RIIβ Holoenzyme.
Article in PLoS biology, 2015. 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.
- A small molecule reduces both parkinsonism and l-dopa-induced dyskinesia in animal models of Parkinson's disease.Science translational medicine · 2026Article
- Hedgehog pathway activity downstream of Smoothened is regulated specifically by basal ciliary PKA.Cellular & molecular biology letters · 2026Article
- Crustacean Protein Kinases A and C: Bioinformatic Characterization in Decapods and Other Non-Model Organisms.International journal of molecular sciences · 2025Article
- Allosteric modulation of protein kinase A in individuals affected by NLPD-PKA, a neurodegenerative disease in which the PRKAR1B L50R variant is expressed.The FEBS journal · 2025Article
- The microprotein C16orf74/MICT1 promotes thermogenesis in brown adipose tissue.The EMBO journal · 2025Article
- Phosphatases Control the Duration and Range of cAMP/PKA Microdomains.Function (Oxford, England) · 2025Article
- Interaction networks explain holoenzyme allostery in Protein Kinase A.Kinases and phosphatases · 2023Article
- Article
- A multiscale model of the regulation of aquaporin 2 recycling.NPJ systems biology and applications · 2022Article
- Control of the Hedgehog pathway by compartmentalized PKA in the primary cilium.Science China. Life sciences · 2022Review
- Assaying Protein Kinase A Activity Using a FRET-Based Sensor Purified from Mammalian Cells.Methods in molecular biology (Clifton, N.J.) · 2022Article
- Breadth and Specificity in Pleiotropic Protein Kinase A Activity and Environmental Responses.Frontiers in cell and developmental biology · 2022Review
- Article
- Depolarization induces nociceptor sensitization by CaV1.2-mediated PKA-II activation.The Journal of cell biology · 2021Article
- PKA-RIIβ autophosphorylation modulates PKA activity and seizure phenotypes in mice.Communications biology · 2021Article
- Two PKA RIα holoenzyme states define ATP as an isoform-specific orthosteric inhibitor that competes with the allosteric activator, cAMP.Proceedings of the National Academy of Sciences of the United States of America · 2019Article
- Dynamic allostery-based molecular workings of kinase:peptide complexes.Proceedings of the National Academy of Sciences of the United States of America · 2019Article
- Protein kinase A activation: Something new under the sun?The Journal of cell biology · 2018Article
- PKA-RII subunit phosphorylation precedes activation by cAMP and regulates activity termination.The Journal of cell biology · 2018Article
- Molecular mechanisms of detection and discrimination of dynamic signals.Scientific reports · 2018Article
Corrections and comments
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Authors and funding
8 authors at 2 institutions in 2 countries.
Funding
Abstract
To provide tight spatiotemporal signaling control, the cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA) holoenzyme typically nucleates a macromolecular complex or a "PKA signalosome." Using the RIIβ holoenzyme as a prototype, we show how autophosphorylation/dephosphorylation of the RIIβ subunit, as well as cAMP and metal ions, contribute to the dynamics of PKA signaling. While we showed previously that the RIIβ holoenzyme could undergo a single turnover autophosphorylation with adenosine triphosphate and magnesium (MgATP) and trap both products in the crystal lattice, we asked here whether calcium could trap an ATP:RIIβ holoenzyme since the RIIβ holoenzyme is located close to ion channels. The 2.8Å structure of an RIIβp2:C2:(Ca2ADP)2 holoenzyme, supported by biochemical and biophysical data, reveals a trapped single phosphorylation event similar to MgATP. Thus, calcium can mediate a single turnover event with either ATP or adenosine-5'-(β,γ-imido)triphosphate (AMP-PNP), even though it cannot support steady-state catalysis efficiently. The holoenzyme serves as a "product trap" because of the slow off-rate of the pRIIβ subunit, which is controlled by cAMP, not by phosphorylation of the inhibitor site. By quantitatively defining the RIIβ signaling cycle, we show that release of pRIIβ in the presence of cAMP is reduced by calcium, whereas autophosphorylation at the phosphorylation site (P-site) inhibits holoenzyme reassociation with the catalytic subunit. Adding a single phosphoryl group to the preformed RIIβ holoenzyme thus creates a signaling cycle in which phosphatases become an essential partner. This previously unappreciated molecular mechanism is an integral part of PKA signaling for type II holoenzymes.
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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.