Crystal structures of human calcineurin and the human FKBP12–FK506–calcineurin complex

@article{Kissinger1995CrystalSO,
  title={Crystal structures of human calcineurin and the human FKBP12–FK506–calcineurin complex},
  author={Charles Kissinger and Hans E. Parge and Daniel R. Knighton and Cristina T. Lewis and Laura A. Pelletier and Anna Tempczyk and Vincent Jacob Kalish and Kathleen D. Tucker and Richard E. Showalter and Ellen W Moomaw and Louis No{\"e}l Gastinel and Noriyuki Habuka and Xinghai Chen and Fausto C Maldonado and Jonathan Barker and Russell J. Bacquet and J Ernest Villafranca},
  journal={Nature},
  year={1995},
  volume={378},
  pages={641-644}
}
CALCINEURIN (CaN) is a calcium- and ca 1modulin-dependent protein serine/threonine phosphatase which is critical for several important cellular processes, including T-cell activation1. CaN is the target of the immunosuppressive drugs cyclosporin A and FK506, which inhibit CaN after forming complexes with cyto-plasmic binding proteins (cyclophilin and FKBP12, respectively)2. We report here the crystal structures of full-length human CaN at 2.1 Å resolution and of the complex of human CaN with… 
Crystal structure of calcineurin–cyclophilin–cyclosporin shows common but distinct recognition of immunophilin–drug complexes
  • Q. Huai, Hwa-young Kim, H. Ke
  • Chemistry, Biology
    Proceedings of the National Academy of Sciences of the United States of America
  • 2002
TLDR
The comparison of CyPA-CsA-CN with FKBP-FK506-CN significantly contributes to understanding the molecular basis of regulation of CN activity by the immunophilin–immunosuppressant.
Calcineurin. Structure, function, and inhibition.
TLDR
The X-ray structure of an FKPB12-FK506-calcineurin AB ternary complex reveals that FKBP12-FX506 binds in a hydophobic groove between the calcineur in A catalytic and the regulatory B subunit, in accord with biochemical and genetic studies on inhibitor action.
Crystal structure of human calcineurin complexed with cyclosporin A and human cyclophilin
  • Lei Jin, S. Harrison
  • Chemistry, Biology
    Proceedings of the National Academy of Sciences of the United States of America
  • 2002
TLDR
The crystal structure of a Cyp/CsA/Cn ternary complex is reported, which accounts clearly for the effects of mutations in Cn on CsA-resistance and for the way modifications ofCsA alter immunosuppressive activity.
Structures of calcineurin and its complexes with immunophilins-immunosuppressants.
  • H. Ke, Q. Huai
  • Biology, Chemistry
    Biochemical and biophysical research communications
  • 2003
Competitive and slow-binding inhibition of calcineurin by drug x immunophilin complexes.
TLDR
Results are consistent with the hypothesis that both classes of drug x immunophilin complexes interact with a common locus on CN which excludes phosphopeptide binding in the enzyme's active site.
Calcineurin: form and function.
TLDR
This review provides a comprehensive examination of the biological roles of calcineurin and reviews aspects related to its structure and catalytic mechanism.
Synergism between the Calmodulin-binding and Autoinhibitory Domains on Calcineurin Is Essential for the Induction of Their Phosphatase Activity*
TLDR
It is shown here that the binding of CaM to CN may affect the conformation of CN at both the CaM-binding and the autoinhibitory domains and that this is critical for activation of CN to dephosphorylate NF-AT.
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References

SHOWING 1-10 OF 24 REFERENCES
Regulation of calcineurin phosphatase activity and interaction with the FK-506.FK-506 binding protein complex.
TLDR
It is shown here that a region within the catalytic subunit that regulates phosphatase activity, the autoinhibitory domain, also regulates the Ca(2+)-dependent interaction of calcineurin with the FK-506, an essential component of the T-cell receptor signal transduction pathway.
Calcium Regulation of Calcineurin Phosphatase Activity by Its B Subunit and Calmodulin
TLDR
Kinetic analysis showed that although the purified mutants had no activity in the absence of calcium, they were less dependent than the wild-type enzyme on calcium and calmodulin for activity, consistent with synergistic activation of calcineurin by Ca acting through both CaM and the B subunit.
Cyclophilin residues that affect noncompetitive inhibition of the protein serine phosphatase activity of calcineurin by the cyclophilin.cyclosporin A complex.
TLDR
With this assay, it is determined that human cyclophilin A complexed with the immunosuppressive drug cyclosporin A is a noncompetitive inhibitor of calcineurin phosphatase activity.
Atomic structure of FKBP-FK506, an immunophilin-immunosuppressant complex
The structure of the human FK506 binding protein (FKBP), complexed with the immunosuppressant FK506, has been determined to 1.7 angstroms resolution by x-ray crystallography. The conformation of the
Cyclosporin-mediated inhibition of bovine calcineurin by cyclophilins A and B.
  • S. Swanson, T. Born, F. Rusnak
  • Biology, Chemistry
    Proceedings of the National Academy of Sciences of the United States of America
  • 1992
TLDR
In all inhibition assays with [32P]casein or [Ser(32P)15]RII, the concentration of calcineurin required for measurable phosphatase activity is such that these complexes behave as tight-binding inhibitors of calcinesurin, and steady-state kinetics cannot be used to assess inhibition patterns or Ki values.
Calcineurin: a calcium- and calmodulin-binding protein of the nervous system.
TLDR
The dual interaction of calcineurin A with two different Ca2+-binding components and the high affinity of calcinesurin forCa2+ suggest a possible role for calcineURin in the regulation of free Ca2+, which may thereby modulate the release and action of neurotransmitters.
Identification of an autoinhibitory domain in calcineurin.
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