Evidence map›Paper›PMID 37745542›Full record

ArticlebioRxiv : the preprint server for biology2023

The αC-β4 loop controls the allosteric cooperativity between nucleotide and substrate in the catalytic subunit of protein kinase A.

Cristina Olivieri, Yingjie Wang, Caitlin Walker, Manu V Subrahmanian, Kim N Ha, David A Bernlohr, Jiali Gao, Carlo Camilloni, Michele Vendruscolo, Susan S Taylor and 1 more

Open access · greenAbstract readPreprint
PubMed Full text at PMC Publisher
In one paragraph

Article in bioRxiv : the preprint server for biology, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

0numbers the graph read from it
0cells of the map it votes in
0citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

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.

2 · The registry

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.

3 · Its place in the literature

Who cites it

0 citing papers in PubMed, 7 citations in OpenAlex.

No citing paper in PubMed yet.

4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

11 authors at 4 institutions in 2 countries.

Cristina OlivieriDepartment of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, MN 55455, USA.
Yingjie WangDepartment of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, MN 55455, USA.
Caitlin WalkerDepartment of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, MN 55455, USA.
Manu V SubrahmanianDepartment of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, MN 55455, USA.
Kim N HaDepartmenf of Chemistry and Biochemistry, St. Catherine University, MN 55105, USA.
David A BernlohrDepartment of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, MN 55455, USA.
Jiali GaoDepartment of Chemistry and Supercomputing Institute, University of Minnesota, MN 55455, USA.
Carlo CamilloniDepartment of Chemistry, University of Cambridge, Cambridge CB2 1EW, UK.
Michele VendruscoloDepartment of Chemistry, University of Cambridge, Cambridge CB2 1EW, UK.
Susan S TaylorDepartment of Pharmacology, University of California at San Diego, CA 92093, USA.
Gianluigi VegliaDepartment of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, MN 55455, USA.
University of Minnesota · USUniversity of Cambridge · GBSt. Catherine University · USUniversity of California San Diego · US

Funding

Lessons Learned from PKA: Assembly of Dynamic Macromolecular SwitchesR35GM130389 · NIGMS · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI SUSAN S. TAYLOR · 2019 to 2026
$5.7M
Mapping Allosteric Cooperativity in Protein KinasesR01GM100310 · NIGMS · UNIVERSITY OF MINNESOTA · PI VEGLIA, GIANLUIGI · 2012 to 2019
$4.3M
Structural Basis of Dilated CardiomyopathyR01HL144130 · NHLBI · UNIVERSITY OF MINNESOTA · PI VEGLIA, GIANLUIGI · 2018 to 2021
$1.5M
NHLBI NIH HHS R01 HL144130NIGMS NIH HHS R01 GM100310NIGMS NIH HHS R35 GM130389
6 · The paper itself

Abstract

Allosteric cooperativity between ATP and substrates is a prominent characteristic of the cAMP-dependent catalytic (C) subunit of protein kinase A (PKA). Not only this long-range synergistic action is involved in substrate recognition and fidelity, but it is likely to regulate PKA association with regulatory subunits and other binding partners. To date, a complete understanding of the molecular determinants for this intramolecular mechanism is still lacking. Here, we used an integrated NMR-restrained molecular dynamics simulations and a Markov Model to characterize the free energy landscape and conformational transitions of the catalytic subunit of protein kinase A (PKA-C). We found that the apo-enzyme populates a broad free energy basin featuring a conformational ensemble of the active state of PKA-C (ground state) and other basins with lower populations (excited states). The first excited state corresponds to a previously characterized inactive state of PKA-C with the αC helix swinging outward. The second excited state displays a disrupted hydrophobic packing around the regulatory (R) spine, with a flipped configuration of the F100 and F102 residues at the tip of the αC-β4 loop. To experimentally validate the second excited state, we mutated F100 into alanine and used NMR spectroscopy to characterize the binding thermodynamics and structural response of ATP and a prototypical peptide substrate. While the activity of PKA-C

Indexed as

allosteric mutationsbinding cooperativitycAMP-dependent protein kinase AProtein Kinases

Identifiers

PMID37745542
PMCPMC10515842
OpenAlexW4386763235

What OpenQuestion holds

Textmetadata
LicenceCC BY
Read underepoch 390

Registered trials

None linked

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.