ArticleProceedings of the National Academy of Sciences of the United States of America2018
Switching of the folding-energy landscape governs the allosteric activation of protein kinase A.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed.
- Transcriptome-wide mapping reveals an RNA-dependent mechanism of platinum cancer drugs.bioRxiv : the preprint server for biology · 2025Article
- Recurrent Acrodysostosis-Related PKA RIα Mutant Reveals a Novel Mechanism of Aberrant PKA Deactivation.Journal of molecular biology · 2025Article
- One-pot dual protein labeling for simultaneous mechanical and fluorescent readouts in optical tweezers.Protein science : a publication of the Protein Society · 2025Article
- 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
- The cofactor-dependent folding mechanism of Drosophila cryptochrome revealed by single-molecule pulling experiments.Nature communications · 2023Article
- Detecting Förster resonance energy transfer in living cells by conventional and spectral flow cytometry.Cytometry. Part A : the journal of the International Society for Analytical Cytology · 2022Article
- Using Optical Tweezers to Dissect Allosteric Communication Networks in Protein Kinases.Methods in molecular biology (Clifton, N.J.) · 2022Article
- Using Optical Tweezers to Monitor Allosteric Signals Through Changes in Folding Energy Landscapes.Methods in molecular biology (Clifton, N.J.) · 2022Article
- Facile tethering of stable and unstable proteins for optical tweezers experiments.Biophysical journal · 2021Article
- Article
- Intrinsic dynamics is evolutionarily optimized to enable allosteric behavior.Current opinion in structural biology · 2020Review
- 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
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Authors and funding
7 authors.
Funding
Abstract
Protein kinases are dynamic molecular switches that sample multiple conformational states. The regulatory subunit of PKA harbors two cAMP-binding domains [cyclic nucleotide-binding (CNB) domains] that oscillate between inactive and active conformations dependent on cAMP binding. The cooperative binding of cAMP to the CNB domains activates an allosteric interaction network that enables PKA to progress from the inactive to active conformation, unleashing the activity of the catalytic subunit. Despite its importance in the regulation of many biological processes, the molecular mechanism responsible for the observed cooperativity during the activation of PKA remains unclear. Here, we use optical tweezers to probe the folding cooperativity and energetics of domain communication between the cAMP-binding domains in the apo state and bound to the catalytic subunit. Our study provides direct evidence of a switch in the folding-energy landscape of the two CNB domains from energetically independent in the apo state to highly cooperative and energetically coupled in the presence of the catalytic subunit. Moreover, we show that destabilizing mutational effects in one CNB domain efficiently propagate to the other and decrease the folding cooperativity between them. Taken together, our results provide a thermodynamic foundation for the conformational plasticity that enables protein kinases to adapt and respond to signaling molecules.
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