ArticleJournal of molecular biology2016
Structure of a PKA RIα Recurrent Acrodysostosis Mutant Explains Defective cAMP-Dependent Activation.
Article in Journal of molecular biology, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
22 citing papers in PubMed, 28 citations in OpenAlex.
- Acrodysostosis type 1: mechanisms explaining PRKAR1A mutation mediated dysregulation of cAMP-PKA signalling.Cell communication and signaling : CCS · 2026Review
- Functional divergence of protein kinase A regulatory subunit Iβ variants: the importance of N3A motifs in PKA regulation.The FEBS journal · 2026Article
- Conformational Dynamics and Allostery in the cAMP-Protein Kinase A Signalosome.Advances in experimental medicine and biology · 2026Review
- Recurrent Acrodysostosis-Related PKA RIα Mutant Reveals a Novel Mechanism of Aberrant PKA Deactivation.Journal of molecular biology · 2025Article
- Aberrant phase separation of two PKA RIβ neurological disorder mutants leads to mechanistically distinct signaling deficits.Cell reports · 2025Article
- Local and distal changes in dynamics are caused by an L205R Cushing's syndrome mutant in PRKACA.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- A mutation in the PRKAR1B gene drives pathological mechanisms of neurodegeneration across species.Brain : a journal of neurology · 2024Article
- Molecular determinants and signaling effects of PKA RIα phase separation.Molecular cell · 2024Article
- A divergent protein kinase A regulatory subunit essential for morphogenesis of the human pathogen Leishmania.PLoS pathogens · 2024Article
- Phosphodiesterase 4D activity in acrodysostosis-associated neural pathology: too much or too little?Brain communications · 2024Review
- Interaction networks explain holoenzyme allostery in Protein Kinase A.Kinases and phosphatases · 2023Article
- Impaired cAMP processivity by phosphodiesterase-protein kinase A complexes in acrodysostosis.Frontiers in molecular biosciences · 2023Article
- The Tails of Protein Kinase A.Molecular pharmacology · 2022Review
- Using Optical Tweezers to Dissect Allosteric Communication Networks in Protein Kinases.Methods in molecular biology (Clifton, N.J.) · 2022Article
- The cAMP-signaling cancers: Clinically-divergent disorders with a common central pathway.Frontiers in endocrinology · 2022Review
- GPharmacological reviews · 2021Review
- 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
- Cardiac function modulation depends on the A-kinase anchoring protein complex.Journal of cellular and molecular medicine · 2019Review
- 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
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
9 authors at 3 institutions in 2 countries.
Funding
Abstract
Most disease-related mutations that impair cAMP protein kinase A (PKA) signaling are present within the regulatory (R) PKA RI alpha-subunit (RIα). Although mutations in the PRKAR1A gene are linked to Carney complex (CNC) disease and, more recently, to acrodysostosis-1 (ACRDYS1), the two diseases show contrasting phenotypes. While CNC mutations cause increased PKA activity, ACRDYS1 mutations result in decreased PKA activity and cAMP resistant holoenzymes. Mapping the ACRDYS1 disease mutations reveals their localization to the second of two tandem cAMP-binding (CNB) domains (CNB-B), and here, we characterize a recurrent deletion mutant where the last 14 residues are missing. The crystal structure of a monomeric form of this mutant (RIα92-365) bound to the catalytic (C)-subunit reveals the dysfunctional regions of the RIα subunit. Beyond the missing residues, the entire capping motif is disordered (residues 357-379) and explains the disrupted cAMP binding. Moreover, the effects of the mutation extend far beyond the CNB-B domain and include the active site and N-lobe of the C-subunit, which is in a partially open conformation with the C-tail disordered. A key residue that contributes to this crosstalk, D267, is altered in our structure, and we confirmed its functional importance by mutagenesis. In particular, the D267 interaction with Arg241, a residue shown earlier to be important for allosteric regulation, is disrupted, thereby strengthening the interaction of D267 with the C-subunit residue Arg194 at the R:C interface. We see here how the switch between active (cAMP-bound) and inactive (holoenzyme) conformations is perturbed and how the dynamically controlled crosstalk between the helical domains of the two CNB domains is necessary for the functional regulation of PKA activity.
Indexed as
Identifiers
What OpenQuestion holds
Registered trials
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.