ArticleProceedings of the National Academy of Sciences of the United States of America2013
Signaling through dynamic linkers as revealed by PKA.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 57 papers.
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Who cites it
57 citing papers in PubMed.
- Recurrent Acrodysostosis-Related PKA RIα Mutant Reveals a Novel Mechanism of Aberrant PKA Deactivation.Journal of molecular biology · 2025Article
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- Myofilament-associated proteins with intrinsic disorder (MAPIDs) and their resolution by computational modeling.Quarterly reviews of biophysics · 2023Review
- ATP-competitive inhibitors modulate the substrate binding cooperativity of a kinase by altering its conformational entropy.Science advances · 2022Article
- Molecular mechanism of glycolytic flux control intrinsic to human phosphoglycerate kinase.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- 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
- CHESPA/CHESCA-SPARKY: automated NMR data analysis plugins for SPARKY to map protein allostery.Bioinformatics (Oxford, England) · 2021Article
- Biochemical and structural characterization of analogs of MRE11 breast cancer-associated mutant F237C.Scientific reports · 2021Article
- Mechanism of allosteric inhibition in theThe Journal of biological chemistry · 2020Article
- Allosteric pluripotency as revealed by protein kinase A.Science advances · 2020Article
- Article
- 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
- Remodeling of the interdomain allosteric linker upon membrane binding of CCTα pulls its active site close to the membrane surface.The Journal of biological chemistry · 2019Article
- Conformational equilibrium defines the variable induction of the multidrug-binding transcriptional repressor QacR.Proceedings of the National Academy of Sciences of the United States of America · 2019Article
- Novel Fluorescent Cyclic Nucleotide Derivatives to Study CNG and HCN Channel Function.Biophysical journal · 2019Article
- Identifying coupled clusters of allostery participants through chemical shift perturbations.Proceedings of the National Academy of Sciences of the United States of America · 2019Article
- Hydrophobic alkyl chains substituted to the 8-position of cyclic nucleotides enhance activation of CNG and HCN channels by an intricate enthalpy - entropy compensation.Scientific reports · 2018Article
- Towards simple kinetic models of functional dynamics for a kinase subfamily.Nature chemistry · 2018Article
- 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
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6 authors.
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Abstract
Protein kinase A (PKA) is a prototype of multidomain signaling proteins functioning as allosteric conformational switches. Allosteric transitions have been the subject of extensive structural and dynamic investigations focusing mainly on folded domains. However, the current understanding of the allosteric role of partially unstructured linkers flanking globular domains is limited. Here, we show that a dynamic linker in the regulatory subunit (R) of PKA serves not only as a passive covalent thread, but also as an active allosteric element that controls activation of the kinase subunit (C) by tuning the inhibitory preequilibrium of a minimally populated intermediate (apo R). Apo R samples both C-binding competent (inactive) and incompetent (active) conformations within a nearly degenerate free-energy landscape and such degeneracy maximally amplifies the response to weak (∼2RT), but conformation-selective interactions elicited by the linker. Specifically, the R linker that in the R:C complex docks in the active site of C in apo R preferentially interacts with the C-binding incompetent state of the adjacent cAMP-binding domain (CBD). These unanticipated findings imply that the formation of the intermolecular R:C inhibitory interface occurs at the expense of destabilizing the intramolecular linker/CBD interactions in R. A direct implication of this model, which was not predictable solely based on protein structure, is that the disruption of a linker/CBD salt bridge in the R:C complex unexpectedly leads to increased affinity of R for C. The linker includes therefore sites of R:C complex frustration and frustration-relieving mutations enhance the kinase inhibitory potency of R without compromising its specificity.
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