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.

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.