The linker region joining the catalytic and the regulatory domains of CnA is essential for binding to NFAT.
Calcineurin (CN) is an important regulator of developmental processes and in adults controls the immune response through its regulation of nuclear factor of activated T cells (NFAT). The physical interaction between CN and NFATs is an essential step in the activation of NFAT-dependent genes by calcium signals. Using deletional and substitutional analyses, we have identified a 13-amino acid region within CN that is essential for the interaction with NFAT and with two other CN-binding proteins, AKAP79 and Cabin-1. The interaction of CN with these proteins is selectively disrupted by substitution of specific amino acid residues within this region, indicating that NFAT and other CN-interacting proteins bind differentially to CN. This selectivity suggests that the region identified in CN could be a potential molecular target for immunosuppressive and other therapeutic interventions in diseases involving the CN/NFAT pathway.
Rodríguez
Antonio
A
Centro Nacional de Investigaciones Cardiovasculares (CNIC), Ronda de Poniente 5, Tres Cantos, Madrid 28760, Spain.
Martínez-Martínez
Sara
S
López-Maderuelo
Ma Dolores
MD
Ortega-Pérez
Inmaculada
I
Redondo
Juan Miguel
JM
D054758:A Kinase Anchor Proteins; D021581:Active Transport, Cell Nucleus; D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry; D019703:Calcineurin / Q000737:chemistry*; D002118:Calcium / Q000378:metabolism; D020134:Catalytic Domain; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000737:chemistry*; D017353:Gene Deletion; D005982:Glutathione Transferase / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D007166:Immunosuppressive Agents / Q000737:chemistry; D008856:Microscopy, Fluorescence; D008954:Models, Biological; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins / Q000737:chemistry*; D009842:Oligopeptides / Q000737:chemistry; D010957:Plasmids / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D014157:Transcription Factors / Q000737:chemistry*; D014162:Transfection
D054758:A Kinase Anchor Proteins; C487775:AKAP5 protein, human; D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; D007166:Immunosuppressive Agents; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D009842:Oligopeptides; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; C468309:cabin-1; D005982:Glutathione Transferase; D019703:Calcineurin; D002118:Calcium