4F0Z

Crystal Structure of Calcineurin in Complex with the Calcineurin-Inhibiting Domain of the African Swine Fever Virus Protein A238L

Summary for 4F0Z

• Entry DOI: 10.2210/pdb4f0z/pdb
• Related: 1AUI 1M63 1MF8 1TCO 2P6B 3LL8
• Descriptor: Serine/threonine-protein phosphatase 2B catalytic subunit alpha isoform, Calcineurin subunit B type 1, Ankyrin repeat domain-containing protein A238L, ... (6 entities in total)
• Functional Keywords: ef-hand, phosphatase, pxixit, lxvp, calcium signaling, transcription regulation, t-cell activation, calcineurin inhibition, calmodulin, rcan, nfat, heart, nucleus, skeletal muscle, ion channels, hydrolase-protein binding complex, hydrolase/protein binding
• Biological source: Homo sapiens (human); More
• Cellular location: Nucleus (By similarity): Q08209; Host nucleus: O36972
• Total number of polymer chains: 3
• Total formula weight: 68184.10

Authors

Grigoriu, S.,Peti, W.,Page, R. (deposition date: 2012-05-05, release date: 2013-03-06, Last modification date: 2023-09-13)

Primary citation

Grigoriu, S.,Bond, R.,Cossio, P.,Chen, J.A.,Ly, N.,Hummer, G.,Page, R.,Cyert, M.S.,Peti, W.
The molecular mechanism of substrate engagement and immunosuppressant inhibition of calcineurin.
Plos Biol., 11:e1001492-e1001492, 2013

PubMed 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.

PubMed: 23468591
DOI: 10.1371/journal.pbio.1001492

Experimental method

X-RAY DIFFRACTION (1.7 Å)