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Crystal Structure of Calcineurin in Complex with the Calcineurin-Inhibiting Domain of the African Swine Fever Virus Protein A238LCrystal Structure of Calcineurin in Complex with the Calcineurin-Inhibiting Domain of the African Swine Fever Virus Protein A238L
Structural highlights
Function[PP2BA_HUMAN] Calcium-dependent, calmodulin-stimulated protein phosphatase. This subunit may have a role in the calmodulin activation of calcineurin. Dephosphorylates DNM1L, HSPB1 and SSH1.[1] [2] [VF238_ASFM2] Inhibits activation of the NF-kappa-B transcription factor by preventing binding of NF-kappa-B subunits RELA and NFKB3 to DNA. Inhibits also the activity of the calcium/calmodulin-regulated phosphatase calcineurin (By similarity). [CANB1_HUMAN] Regulatory subunit of calcineurin, a calcium-dependent, calmodulin stimulated protein phosphatase. Confers calcium sensitivity. Publication Abstract from PubMedSer/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/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 A 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. The molecular mechanism of substrate engagement and immunosuppressant inhibition of calcineurin.,Grigoriu S, Bond R, Cossio P, Chen JA, Ly N, Hummer G, Page R, Cyert MS, Peti W PLoS Biol. 2013 Feb;11(2):e1001492. doi: 10.1371/journal.pbio.1001492. Epub 2013 , Feb 26. PMID:23468591[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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