Calcineurin Undergoes a Conformational Switch Evoked via Peptidyl-Prolyl Isomerization

Alicia Guasch; Álvaro Aranguren-Ibáñez; Rosa Pérez-Luque; David Aparicio; Sergio Martínez-Høyer; M Carmen Mulero; Eva Serrano-Candelas; Mercè Pérez-Riba; Ignacio Fita

doi:10.1371/journal.pone.0134569

Calcineurin Undergoes a Conformational Switch Evoked via Peptidyl-Prolyl Isomerization

PLoS One. 2015 Aug 6;10(8):e0134569. doi: 10.1371/journal.pone.0134569. eCollection 2015.

Authors

Alicia Guasch¹, Álvaro Aranguren-Ibáñez², Rosa Pérez-Luque¹, David Aparicio¹, Sergio Martínez-Høyer², M Carmen Mulero², Eva Serrano-Candelas², Mercè Pérez-Riba², Ignacio Fita¹

Affiliations

¹ Institut de Biologia Molecular de Barcelona (IBMB-CSIC), Parc Científic, Baldiri Reixac 10, 08028, Barcelona, Spain.
² Human Molecular Genetics Laboratory, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), Gran Via de L'Hospitalet 199, L'Hospitalet de Llobregat, 08908, Barcelona, Spain.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amino Acid Sequence
Binding Sites
Calcineurin / chemistry
Calcineurin / genetics
Calcineurin / metabolism*
Catalytic Domain
Crystallography, X-Ray
Cyclophilin A / metabolism
Cyclosporine / chemistry
Cyclosporine / metabolism
HEK293 Cells
Humans
Isomerism
Molecular Dynamics Simulation
Molecular Sequence Data
NFATC Transcription Factors / chemistry
NFATC Transcription Factors / metabolism
Protein Binding
Protein Isoforms / chemistry
Protein Isoforms / genetics
Protein Isoforms / metabolism
Recombinant Proteins / biosynthesis
Recombinant Proteins / chemistry
Recombinant Proteins / isolation & purification
Sequence Alignment
Tacrolimus Binding Protein 1A / metabolism

Substances

NFATC Transcription Factors
Protein Isoforms
Recombinant Proteins
Cyclosporine
Calcineurin
Cyclophilin A
Tacrolimus Binding Protein 1A

Grants and funding

This work was supported by grants SAF2009-08216-BFU2012-36827 from Ministerio de Ciencia e Innovación and 2009SGR1490-2014SGR987 from the Generalitat de Catalunya. A. A.-I. was a recipient of an FI PhD fellowship from Generalitat de Catalunya.