ArticlePLoS biology2015
Mapping the Free Energy Landscape of PKA Inhibition and Activation: A Double-Conformational Selection Model for the Tandem cAMP-Binding Domains of PKA RIα.
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 21 papers.
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Who cites it
21 citing papers in PubMed, 43 citations in OpenAlex.
- A cryptic symmetry switch allosterically controls how the PF4 self-protein turns into a pathogenic antigen.Nature communications · 2026Article
- Recurrent Acrodysostosis-Related PKA RIα Mutant Reveals a Novel Mechanism of Aberrant PKA Deactivation.Journal of molecular biology · 2025Article
- N3A motifs in RIβ mediate allosteric crosstalk between cAMP and ATP in PKA activation.Protein science : a publication of the Protein Society · 2025Article
- Purine nucleosides replace cAMP in allosteric regulation of PKA in trypanosomatid pathogens.eLife · 2024Article
- Probing ligand selectivity in pathogens.eLife · 2023Article
- Interaction networks explain holoenzyme allostery in Protein Kinase A.Kinases and phosphatases · 2023Article
- Conformational changes in protein kinase A along its activation cycle are rooted in the folding energetics of cyclic-nucleotide binding domains.The Journal of biological chemistry · 2023Article
- Article
- Using Optical Tweezers to Monitor Allosteric Signals Through Changes in Folding Energy Landscapes.Methods in molecular biology (Clifton, N.J.) · 2022Article
- State-selective frustration as a key driver of allosteric pluripotency.Chemical science · 2021Article
- Noncanonical protein kinase A activation by oligomerization of regulatory subunits as revealed by inherited Carney complex mutations.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- Article
- Mechanism of allosteric inhibition in theThe Journal of biological chemistry · 2020Article
- Allosteric pluripotency as revealed by protein kinase A.Science advances · 2020Article
- Allosteric inhibition explained through conformational ensembles sampling distinct "mixed" states.Computational and structural biotechnology journal · 2020Review
- Exploring the structural basis of conformational heterogeneity and autoinhibition of human cGMP-specific protein kinase Iα through computational modelling and molecular dynamics simulations.Computational and structural biotechnology journal · 2020Article
- 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
- Disrupting the Allosteric Interaction between the Plasmodium falciparum cAMP-dependent Kinase and Its Regulatory Subunit.The Journal of biological chemistry · 2016Article
- Unidirectional allostery in the regulatory subunit RIα facilitates efficient deactivation of protein kinase A.Proceedings of the National Academy of Sciences of the United States of America · 2016Article
- Chemical shift imprint of intersubunit communication in a symmetric homodimer.Proceedings of the National Academy of Sciences of the United States of America · 2016Article
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Authors and funding
6 authors at 2 institutions in 2 countries.
Funding
Abstract
Protein Kinase A (PKA) is the major receptor for the cyclic adenosine monophosphate (cAMP) secondary messenger in eukaryotes. cAMP binds to two tandem cAMP-binding domains (CBD-A and -B) within the regulatory subunit of PKA (R), unleashing the activity of the catalytic subunit (C). While CBD-A in RIα is required for PKA inhibition and activation, CBD-B functions as a "gatekeeper" domain that modulates the control exerted by CBD-A. Preliminary evidence suggests that CBD-B dynamics are critical for its gatekeeper function. To test this hypothesis, here we investigate by Nuclear Magnetic Resonance (NMR) the two-domain construct RIα (91-379) in its apo, cAMP2, and C-bound forms. Our comparative NMR analyses lead to a double conformational selection model in which each apo CBD dynamically samples both active and inactive states independently of the adjacent CBD within a nearly degenerate free energy landscape. Such degeneracy is critical to explain the sensitivity of CBD-B to weak interactions with C and its high affinity for cAMP. Binding of cAMP eliminates this degeneracy, as it selectively stabilizes the active conformation within each CBD and inter-CBD contacts, which require both cAMP and W260. The latter is contributed by CBD-B and mediates capping of the cAMP bound to CBD-A. The inter-CBD interface is dispensable for intra-CBD conformational selection, but is indispensable for full activation of PKA as it occludes C-subunit recognition sites within CBD-A. In addition, the two structurally homologous cAMP-bound CBDs exhibit marked differences in their residual dynamics profiles, supporting the notion that conservation of structure does not necessarily imply conservation of dynamics.
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