Title:
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Calcineurin Undergoes a Conformational Switch Evoked via Peptidyl-Prolyl Isomerization
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Author:
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Guasch, Alicia; Aranguren Ibáñez, Álvaro; Pérez Luque, Rosa; Aparicio, David; Martínez Høyer, Sergio; Mulero Roig, María Carmen; Serrano Candelas, Eva; Pérez Riba, Mercè; Fita Rodríguez, Ignasi
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Other authors:
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Universitat de Barcelona |
Abstract:
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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. |
Subject(s):
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-Estructura cristal·lina (Sòlids) -Esterases -Síntesi de pèptids -Isomerització -Interaccions dels medicaments -Layer structure (Solids) -Esterases -Peptide synthesis -Isomerization -Drug interactions |
Rights:
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cc-by (c) Guasch et al., 2015
http://creativecommons.org/licenses/by/3.0/es |
Document type:
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Article Article - Published version |
Published by:
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Public Library of Science (PLoS)
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