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Calcineurin undergoes a conformational switch evoked via peptidyl-prolyl isomerization

AuthorsGuasch, Alicia ; Aranguren-Ibáñez, Álvaro; Pérez-Luque, Rosa ; Aparicio, David ; Martínez-Hoyer, Sergio; Mulero, M. Carmen; Serrano-Candelas, Eva; Pérez-Riba, Mercè; Fita, Ignacio
Issue Date6-Aug-2015
PublisherPublic Library of Science
CitationPLoS ONE 10(8): e0134569 (2015)
AbstractCopyright: © 2015 Guasch et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. 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.
Publisher version (URL)http://dx.doi.org/10.1371/journal.pone.0134569
Identifiersdoi: 10.1371/journal.pone.0134569
issn: 1932-6203
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