title: Calcineurin Undergoes a Conformational Switch Evoked via Peptidyl-Prolyl Isomerization.
abstract: A limited repertoire of PPP family of serine/threonine phosphatases with a highly conserved catalytic domain acts on thousands of protein targets to orchestrate myriad central biological roles. A major structural reorganization of human calcineurin, a ubiquitous Ser/Thr PPP regulated by calcium and calmodulin and targeted by immunosuppressant drugs cyclosporin A and FK506, is unveiled here. The new conformation involves trans- to cis-isomerization of proline in the SAPNY sequence, highly conserved across PPPs, and remodels the main regulatory site where NFATc transcription factors bind. Transitions between cis- and trans-conformations may involve peptidyl prolyl isomerases such as cyclophilin A and FKBP12, which are known to physically interact with and modulate calcineurin even in the absence of immunosuppressant drugs. Alternative conformations in PPPs provide a new perspective on interactions with substrates and other protein partners and may foster development of more specific inhibitors as drug candidates.
authors.affiliation: Institut de Biologia Molecular de Barcelona (IBMB-CSIC), Parc Científic, Baldiri Reixac 10, 08028, Barcelona, Spain.
authors.forename: Alicia
authors.initials: A
authors.lastname: Guasch
authors.affiliation: Human Molecular Genetics Laboratory, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), Gran Via de L'Hospitalet 199, L'Hospitalet de Llobregat, 08908, Barcelona, Spain.
authors.forename: Álvaro
authors.initials: Á
authors.lastname: Aranguren-Ibáñez
authors.affiliation: Institut de Biologia Molecular de Barcelona (IBMB-CSIC), Parc Científic, Baldiri Reixac 10, 08028, Barcelona, Spain.
authors.forename: Rosa
authors.initials: R
authors.lastname: Pérez-Luque
authors.affiliation: Institut de Biologia Molecular de Barcelona (IBMB-CSIC), Parc Científic, Baldiri Reixac 10, 08028, Barcelona, Spain.
authors.forename: David
authors.initials: D
authors.lastname: Aparicio
authors.affiliation: Human Molecular Genetics Laboratory, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), Gran Via de L'Hospitalet 199, L'Hospitalet de Llobregat, 08908, Barcelona, Spain.
authors.forename: Sergio
authors.initials: S
authors.lastname: Martínez-Høyer
authors.affiliation: Human Molecular Genetics Laboratory, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), Gran Via de L'Hospitalet 199, L'Hospitalet de Llobregat, 08908, Barcelona, Spain.
authors.forename: M Carmen
authors.initials: MC
authors.lastname: Mulero
authors.affiliation: Human Molecular Genetics Laboratory, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), Gran Via de L'Hospitalet 199, L'Hospitalet de Llobregat, 08908, Barcelona, Spain.
authors.forename: Eva
authors.initials: E
authors.lastname: Serrano-Candelas
authors.affiliation: Human Molecular Genetics Laboratory, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), Gran Via de L'Hospitalet 199, L'Hospitalet de Llobregat, 08908, Barcelona, Spain.
authors.forename: Mercè
authors.initials: M
authors.lastname: Pérez-Riba
authors.affiliation: Institut de Biologia Molecular de Barcelona (IBMB-CSIC), Parc Científic, Baldiri Reixac 10, 08028, Barcelona, Spain.
authors.forename: Ignacio
authors.initials: I
authors.lastname: Fita
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D019703:Calcineurin / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D021984:Cyclophilin A / Q000378:metabolism; D016572:Cyclosporine / Q000737:chemistry / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007536:Isomerism; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D050778:NFATC Transcription Factors / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000302:isolation & purification; D016415:Sequence Alignment; D022061:Tacrolimus Binding Protein 1A / Q000378:metabolism
chemical_list: D050778:NFATC Transcription Factors; D020033:Protein Isoforms; D011994:Recombinant Proteins; D016572:Cyclosporine; D019703:Calcineurin; D021984:Cyclophilin A; D022061:Tacrolimus Binding Protein 1A