ArticleThe Journal of biological chemistry2014
Using Markov state models to develop a mechanistic understanding of protein kinase A regulatory subunit RIα activation in response to cAMP binding.
Article in The Journal of biological chemistry, 2014. 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.
- N3A motifs in RIβ mediate allosteric crosstalk between cAMP and ATP in PKA activation.Protein science : a publication of the Protein Society · 2025Article
- Electrophysical cardiac remodeling at the molecular level: Insights into ryanodine receptor activation and calcium-induced calcium release from a stochastic explicit-particle model.Biophysical journal · 2024Article
- Fluorescent biosensors illuminate the spatial regulation of cell signaling across scales.The Biochemical journal · 2023Review
- TYROSINE KINASES: COMPLEX MOLECULAR SYSTEMS CHALLENGING COMPUTATIONAL METHODOLOGIES.The European physical journal. B · 2021Article
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- Phase Separation of a PKA Regulatory Subunit Controls cAMP Compartmentation and Oncogenic Signaling.Cell · 2020Article
- Histamine-induced biphasic activation of RhoA allows for persistent RhoA signaling.PLoS biology · 2020Article
- Activation of PKA via asymmetric allosteric coupling of structurally conserved cyclic nucleotide binding domains.Nature communications · 2019Article
- 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
- Switching of the folding-energy landscape governs the allosteric activation of protein kinase A.Proceedings of the National Academy of Sciences of the United States of America · 2018Article
- Norepinephrine stimulates glycogenolysis in astrocytes to fuel neurons with lactate.PLoS computational biology · 2018Article
- Markov models for the elucidation of allosteric regulation.Philosophical transactions of the Royal Society of London. Series B, Biological sciences · 2018Review
- PKA-RII subunit phosphorylation precedes activation by cAMP and regulates activity termination.The Journal of cell biology · 2018Article
- Phosphorylation of protein kinase A (PKA) regulatory subunit RIα by protein kinase G (PKG) primes PKA for catalytic activity in cells.The Journal of biological chemistry · 2018Article
- Switching Cyclic Nucleotide-Selective Activation of Cyclic Adenosine Monophosphate-Dependent Protein Kinase Holoenzyme Reveals Distinct Roles of Tandem Cyclic Nucleotide-Binding Domains.ACS chemical biology · 2017Article
- Molecular Simulations Reveal an Unresolved Conformation of the Type IA Protein Kinase A Regulatory Subunit and Suggest Its Role in the cAMP Regulatory Mechanism.Biochemistry · 2017Article
- Tyrosine Kinase Activation and Conformational Flexibility: Lessons from Src-Family Tyrosine Kinases.Accounts of chemical research · 2017Article
- Structure of a PKA RIα Recurrent Acrodysostosis Mutant Explains Defective cAMP-Dependent Activation.Journal of molecular biology · 2016Article
- Transition path theory analysis of c-Src kinase activation.Proceedings of the National Academy of Sciences of the United States of America · 2016Article
Corrections and comments
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Authors and funding
4 authors.
Funding
Abstract
Protein kinase A (PKA) holoenzyme consists of two catalytic (C) subunits and a regulatory (R) subunit dimer (R(2)C(2)). The kinase is activated by the binding of cAMPs to the two cyclic nucleotide binding domains (CBDs), A and B, on each R-subunit. Despite extensive study, details of the allosteric mechanisms underlying the cooperativity of holoenzyme activation remain unclear. Several Markov state models of PKA-RIα were developed to test competing theories of activation for the R(2)C(2) complex. We found that CBD-B plays an essential role in R-C interaction and promotes the release of the first C-subunit prior to the binding to CBD-A. This favors a conformational selection mechanism for release of the first C-subunit of PKA. However, the release of the second C-subunit requires all four cAMP sites to be occupied. These analyses elucidate R-C heterodimer interactions in the cooperative activation of PKA and cAMP binding and represent a new mechanistic model of R(2)C(2) PKA-RIα activation.
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