ArticlePLoS biology2013
The molecular mechanism of substrate engagement and immunosuppressant inhibition of calcineurin.
Article in PLoS biology, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 92 papers.
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Who cites it
92 citing papers in PubMed, 141 citations in OpenAlex.
- A multivalent docking platform and Rcn1-mediated inhibition control the extent of calcineurin recruitment to the cell division site for the dephosphorylation of multiple cytokinetic proteins.bioRxiv : the preprint server for biology · 2026Article
- Kujiol A Inhibits Interferon-γ and Interleukin-2 Expression and the NFATc2 Interaction with Their Promoters in T Cells.Molecules (Basel, Switzerland) · 2026Article
- The clinical missense variant E282K in PPP3CA/calcineurin shifts substrate dephosphorylation by altering active site recruitment.Nature communications · 2026Article
- Building epigenetic risk scores of opioid use disorder: Insights from human postmortem brain data.Translational psychiatry · 2026Article
- A composite motif in calcimembrin/C16orf74 dictates multimeric dephosphorylation by calcineurin.Nature communications · 2025Article
- Cryo-EM structures of PP2A:B55 with p107 and Eya3 define substrate recruitment.Nature structural & molecular biology · 2025Article
- RCAN1-Mediated Calcineurin Impairment Drives Sympathetic Outflow in Hypertension.Circulation research · 2025Article
- Calcineurin targets that mediateProceedings of the National Academy of Sciences of the United States of America · 2025Article
- Combining cryo-electron microscopy (cryo-EM) with orthogonal solution state methods to define the molecular basis of the phosphoprotein phosphatase family regulation and substrate specificity.Current opinion in structural biology · 2025Review
- Reformulation of the protein databank for real-time search of geometrical attributes of protein structures.Frontiers in molecular biosciences · 2025Article
- A protein phosphatase 1 specificProceedings of the National Academy of Sciences of the United States of America · 2024Article
- RAS and SHOC2 Roles in RAF Activation and Therapeutic Considerations.Annual review of cancer biology · 2024Article
- Article
- The Neurotoxic Effect of Environmental Temperature Variation in Adult Zebrafish (International journal of molecular sciences · 2023Article
- Substrate and phosphorylation site selection by phosphoprotein phosphatases.Trends in biochemical sciences · 2023Review
- Calcineurin associates with centrosomes and regulates cilia length maintenance.Journal of cell science · 2023Article
- African Swine Fever Virus Cysteine Protease pS273R Inhibits Type I Interferon Signaling by Mediating STAT2 Degradation.Journal of virology · 2023Article
- A cellular atlas of calcineurin signaling.Biochimica et biophysica acta. Molecular cell research · 2023Review
- Calcineurin Inhibitor CN585 Exhibits Off-Target Effects in the Human Fungal PathogenJournal of fungi (Basel, Switzerland) · 2022Article
- A polypeptide inhibitor of calcineurin blocks the calcineurin-NFAT signalling pathwayJournal of enzyme inhibition and medicinal chemistry · 2022Article
32 more citing papers are in PubMed but not listed here.
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 4 institutions in 1 country.
Funding
Abstract
Ser/thr phosphatases dephosphorylate their targets with high specificity, yet the structural and sequence determinants of phosphosite recognition are poorly understood. Calcineurin (CN) is a conserved Ca(2+)/calmodulin-dependent ser/thr phosphatase and the target of immunosuppressants, FK506 and cyclosporin A (CSA). To investigate CN substrate recognition we used X-ray crystallography, biochemistry, modeling, and in vivo experiments to study A238L, a viral protein inhibitor of CN. We show that A238L competitively inhibits CN by occupying a critical substrate recognition site, while leaving the catalytic center fully accessible. Critically, the 1.7 Å structure of the A238L-CN complex reveals how CN recognizes residues in A238L that are analogous to a substrate motif, "LxVP." The structure enabled modeling of a peptide substrate bound to CN, which predicts substrate interactions beyond the catalytic center. Finally, this study establishes that "LxVP" sequences and immunosuppressants bind to the identical site on CN. Thus, FK506, CSA, and A238L all prevent "LxVP"-mediated substrate recognition by CN, highlighting the importance of this interaction for substrate dephosphorylation. Collectively, this work presents the first integrated structural model for substrate selection and dephosphorylation by CN and lays the groundwork for structure-based development of new CN inhibitors.
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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.