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==Rat Calcineurin==
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==Structure Rat Calcineurin==
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<StructureSection load='4il1' size='340' side='right' caption='' scene=''>
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<StructureSection load='4il1' size='340' side='right' caption='Rat calcineurin monomer, each of the four chains of the monomer is shown in a different color.' scene=''>
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== Function ==
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<scene name='75/750223/Picture_intro/1'> Calcineurin </scene> is a serine/threonine phosphatase that is activated by [https://en.wikipedia.org/wiki/Calmodulin calmodulin] in a calcium-dependant manner. Calcineurin is the only known calmodulin-activated protein phosphatase. Calcineurin is responsible mainly for dephosphorylating several member of the [https://en.wikipedia.org/wiki/NFAT NFAT] transcription factor family (including NFATc1 through NFATc4).
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<scene name='75/750223/Picture_intro/1'> Calcineurin </scene> is a serine/threonine [https://en.wikipedia.org/wiki/Phosphatase phosphatase] that is activated by [https://en.wikipedia.org/wiki/Calmodulin calmodulin](CaM) in a calcium-dependant manner.
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Also known as Serine threonine phosphatase 2B, it plays an important role in multiple pathways.
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''' Localisation and expression''':
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Calcineurin can modulate the immune response, act on the muscle formation and remodeling as well as on the neuronal plasticity and the cell death.
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It is able to desphosphorylate numerous ion channels and thus modulate the basal excitability of neurons. Calcineurin has also an effect on the synaptic transmission since it affects the release of several neurotransmitters<ref>PMID: 9149541</ref><ref>PMID:PMID: 14623302</ref>.
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Calcineurin is a cytoplasmic protein. The catalytic subunit calcineurin A, posses two major isoforms called calcineurin Aα and Aβ. Calcineurin Aα is widely expressed among tissues especially in the Central Nervous System (CNS). Calcineurin Aβ is rather found in the lymphoid cells.Calcineurin Aβ is therefore involved in the mediation of the immune response (PMID:16888030).
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== Function ==
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Calcineurin is responsible mainly for dephosphorylating several members of the [https://en.wikipedia.org/wiki/NFAT NFAT] transcription factor family (including NFATc1 through NFATc4).
== General structure ==
== General structure ==
<scene name='75/750223/Jw_caln_sec_strcutur/1'>Calcineurin</scene> is a heterodimeric Protein that consits of two subunits. They are called catalytic and regulatory subunit. Four molecules of Calcineurin form an asymmetric complex which leads to a total molecular weight of 370 kDa.
<scene name='75/750223/Jw_caln_sec_strcutur/1'>Calcineurin</scene> is a heterodimeric Protein that consits of two subunits. They are called catalytic and regulatory subunit. Four molecules of Calcineurin form an asymmetric complex which leads to a total molecular weight of 370 kDa.
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The structure presented in this article is the catalytic subunit isoform of the serine/threonine-protein phosphatase 2B in [https://www.ncbi.nlm.nih.gov/UniGene/UGOrg.cgi?TAXID=10116 rattus norvegicus (rat)]. It consists of 521 (http://www.uniprot.org/uniprot/P63329) aminoacids and has a molecular weight of 57 kDa (http://www.uniprot.org/uniprot/P63329).
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The structure presented in this article is the catalytic subunit isoform of the serine/threonine-protein phosphatase 2B in [https://www.ncbi.nlm.nih.gov/UniGene/UGOrg.cgi?TAXID=10116 rattus norvegicus (rat)]. It consists of 521 [http://www.uniprot.org/uniprot/P63329] aminoacids and has a molecular weight of 57 kDa [http://www.uniprot.org/uniprot/P63329].
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The calatytic subunit is subdivided into functional domains which are a <scene name='75/750223/Catalytique_domain_of_chain_a/1'>catalytic domain (here chain A is shown)</scene>, a <scene name='75/750223/Interact_dom_ca/1'>binding domain for the regulary subunit</scene>, a <scene name='75/750223/Calm_bind_dom_ca/1'>calmodulin binding domain </scene> and an <scene name='75/750223/Auto_inh_dom_ca/1'>autoinhibitory domain</scene>.
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The calatytic subunit is subdivided into functional domains which are a <scene name='75/750223/Catalytique_domain_of_chain_a/1'>catalytic domain (here chain A is shown)</scene>, a <scene name='75/750223/Interact_dom_ca/1'>binding domain for the regulary subunit</scene>, a <scene name='75/750223/Calm_bind_dom_ca/1'>calmodulin binding domain </scene> and an <scene name='75/750223/Auto_inh_dom_ca/1'>autoinhibitory domain</scene>.
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The catalytic side includes a residue (green) at position 151 that acts as proton donor and metal binding sites. <Scene name='75/750223/Zink/1'>Zinc</scene> (shown in brown) binds at the position 118, 150, 199 and 281. Four residues are modified with a serine or a tyrosine. At position 2, a N-acetylserine has been found by similarity, as well as a nitrated tyrosine at position 224, and phosphoserine at position 469 and 492.
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The catalytic side includes a residue (green) at position 151 that acts as proton donor and metal binding sites. <Scene name='75/750223/Zink/1'>Zinc</scene> (shown in brown) binds at the position 118, 150, 199 and 281. Iron (blue) interacts at the positions 90, 92 and 118.
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Calcineurin is a cytoplasmic protein. It is widely expressed among tissues especially in the central nervous system (CNS) qnd in lymphoid cells qnd therefore involved in the mediation of the immune response <ref>PMID:16888030</ref>.
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<scene name='75/750223/Modified_residues/1'>Four residues</scene> are modified with a serine or a tyrosine. At position 2, a N-acetylserine has been found by similarity, as well as a nitrated tyrosine at position 224, and phosphoserine at position 469 and 492.
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'''Discovery of the structure:'''
'''Discovery of the structure:'''
[[Image:4il1 multipercentile validation.png|thumb|upright=2|left]]
[[Image:4il1 multipercentile validation.png|thumb|upright=2|left]]
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The structure have been [https://www.ncbi.nlm.nih.gov/pubmed/24018048 published in the year 2013 by Qilu Ye et al.] (PMID:24018048) in [http://www.sciencedirect.com/science/journal/08986568 ''Cellular Signaling'']. For their experiments they used [https://en.wikipedia.org/wiki/X-ray_crystallography#X-ray_diffraction x-ray diffraction]. The [http://www.wwpdb.org/validation/2016/XrayValidationReportHelp PDB validation] obtained a Resolutionof 3.0 Å, a free R-value of 0.273 and a work R-value of 0.241 (http://www.rcsb.org/pdb/explore/explore.do?structureId=4IL1).
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The structure have been [https://www.ncbi.nlm.nih.gov/pubmed/24018048 published in the year 2013 by Qilu Ye et al.] <ref>PMID:24018048</ref> in [http://www.sciencedirect.com/science/journal/08986568 ''Cellular Signaling'']. For their experiments they used [https://en.wikipedia.org/wiki/X-ray_crystallography#X-ray_diffraction x-ray diffraction]. The [http://www.wwpdb.org/validation/2016/XrayValidationReportHelp PDB validation] obtained a Resolutionof 3.0 Å, a free R-value of 0.273 and a work R-value of 0.241 [http://www.rcsb.org/pdb/explore/explore.do?structureId=4IL1].
<br style="clear:both" />
<br style="clear:both" />
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'''Secondary structure:'''
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'''secondary structure:'''
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[[Image:170106 Uniprot SecundaryStructure.png|thumb|upright=4|The secondary structure mostly includes helical structures [http://www.uniprot.org/uniprot/P63100 Uniprot]]]
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[[Image:170106 Uniprot SecundaryStructure.png|thumb|upright=4|The secondary structure mostly includes helical structures]]
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Besides, there are six turns reported in the structure of one chain.
Besides, there are six turns reported in the structure of one chain.
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<br style="clear:both" />
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The Ramachandran blot of Calcineurin [[Image:Ramachandran 4il1.jpg|thumb|left|Ramachandran Plot of 4il1]] has been obtained by [http://mordred.bioc.cam.ac.uk/~rapper/rampage2.php MolProbity of the DUke University]. It plots the torsional angles phi (φ) and psi (ψ) of the molecule and thereby represents the secondary structure. Further information about the Interpretation of this plot can be found at [[Ramachandran Plot]].
<br style="clear:both" />
<br style="clear:both" />
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The Ramachandran blot of Calcineurin [[Image:Ramachandran 4il1.jpg|thumb|left|Ramachandran Plot of 4il1]] has been obtained by [http://mordred.bioc.cam.ac.uk/~rapper/rampage2.php MolProbity of the DUke University]. It plots the torsional angles phi (φ)and psi (ψ)of the molecule and thereby represents the secondary structure. Further information about the Interpretation of this plot can be found at [[Ramachandran Plot]].
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== Principle of action ==
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[[Image:Genes Dev. 2003 Sep 17(18) 2205-32, Figure 1.jpg|thumb|upright=2|Schematic view of the NFAT activation cycle <ref>PMID:12975316</ref>]]
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As a response of receptor tyrosine kinase [https://en.wikipedia.org/wiki/Receptor_tyrosine_kinase(RTK)] activation as well as G protein-coupled receptor [https://en.wikipedia.org/wiki/G_protein%E2%80%93coupled_receptor (GCPR)] activation the [[Phospholipase C]] [https://en.wikipedia.org/wiki/Phospholipase_C (PLC)] catalyse the hydrolysis of [https://en.wikipedia.org/wiki/Phosphatidylinositol_4,5-bisphosphate PIP2] to [https://en.wikipedia.org/wiki/Inositol_trisphosphate IP3] and [https://en.wikipedia.org/wiki/Diglyceride DAG]. IP3 activates the [[Inositol 1,4,5-Trisphosphate Receptor]] and therby leads to an increasing amount of the second Messenger Ca<sup>2+</sup> in the cytoplasma.
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Calcineurin is activated by [http://www.ebi.ac.uk/interpro/potm/2003_3/Page_1.htm Calmodulin], a calcium-binding protein. Calmodulin interacts with the calmodulin-binding/regulatory region of Calcineurin. That binding leads to a conformational change in the autoinhibitory domain and remove it from the active site <ref>PMID:22100452</ref>.
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It has been reported that Calcineurin activates the transcription factor [https://de.wikipedia.org/wiki/NF-AT NFAT] by forming a complex and dephosporylation <ref>PMID:17502104</ref>. Following, the factor enters the nucleus and activates the expression of Interleukin-2.
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<br style="clear:both" />
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== Binding Partners ==
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The main partners of interaction are [https://en.wikipedia.org/wiki/Calmodulin Calmodulin], NFATc1, NFATc2 and NFATc3.
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Many of the calcineurin substrates contain a PxIxIT motif. Among them, beside the phosphorylated forms of NFAT we can also mention cAMP response element binding protein (CREB), PP1, microtubule-associated protein tau and glycogen synthase kinase-3 beta (GSK- 3)<ref>PMID: 17666045</ref><ref>PMID: 22676853</ref><ref>PMID:14701880</ref><ref>PMID: 7515479</ref>.
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<scene name='75/750223/Can_fk506/1'>Calcineurin, here shown in complex with FK506 and FKPB (in pink on the model)</scene> is inhibited by the immunosuppressive drugs tacrolismus (<scene name='75/750223/Tacrolimus/1'>FK506</scene>) or cyclosporine A (CsA). CsA and conduct their therapeutic role thought binding to the [https://en.wikipedia.org/wiki/Immunophilins immunophilins] cyclophilin and FK506 binding protein (FK506BP) respectively. The complexes CsA-cyclophilin and FK506-FK506BP bind then to calcineurin in a calcium-dependent manner thus inhibiting its phosphatase activity. Therefore the addition of these drugs to lymphocytes T prevent NFAT translocation to the nucleus and the subsequent activation its target gene.That's why FK506 and CsA are use in the treatment of various immune-mediated diseases. However since calcineurin is is widely expressed in non-haemopoietic tissues like the kidney and the hearth, both drugs present a long term toxicity and can lead to deleterious effect to these Organs <ref>PMID: 8811062</ref><ref>http://www.uptodate.com/contents/pharmacology-of-cyclosporine-and-tacrolimus</ref>.
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'''Cofactors''':
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== Principle of action ==
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Calcineurin belong to the family of [https://en.wikipedia.org/wiki/Metalloprotein metalloprotein]. To conduct its activity it requires the presence of exposing Fe<sup>3+</sup> and exposing Zn<sup>2+</sup> ions in the active site (one per subunit). Superoxide dismutase has been shown to protect calcineurin from inactivation by preventing Fe<sup>3+</sup> from oxidation. Thus after activation of calcineurin by calmodulin, the AID is displaced from the <scene name='75/750223/Catalytic_core/1'> catalytic core,with phosphate and Fe and Zn ions bound </scene> exposing Fe<sup>3+</sup> to oxidation <ref>PMID: 8837775</ref><ref>Calmodulin and Signal Transduction (p184), Linda J. Van Eldik,D. Martin Watterson (1998)</ref>.
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[[Image:Genes Dev. 2003 Sep 17(18) 2205-32, Figure 1.jpg|thumb|upright=2|Schematic view of the NFAT activation cycle (PMID:12975316)]]
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As a response of receptor tyrosine kinase [https://en.wikipedia.org/wiki/Receptor_tyrosine_kinase(RTK)] activation as well as G protein-coupled receptor [https://en.wikipedia.org/wiki/G_protein%E2%80%93coupled_receptor (GCPR)] activation the [[Phospholipase C]] [https://en.wikipedia.org/wiki/Phospholipase_C (PLC)] catalyse the hydrolysis of [https://en.wikipedia.org/wiki/Phosphatidylinositol_4,5-bisphosphate PIP2] to [https://en.wikipedia.org/wiki/Inositol_trisphosphate IP3] and [https://en.wikipedia.org/wiki/Diglyceride DAG]. IP3 activates the [[Inositol 1,4,5-Trisphosphate Receptor]] and therby leads to an increasing amount of the second Messenger Ca2+ in the cytoplasma.
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Calcineurin is activated by [http://www.ebi.ac.uk/interpro/potm/2003_3/Page_1.htm Calmodulin], a calcium-binding protein. Calmodulin interacts with the calmodulin-binding/regulatory region of Calcineurin. That binding leads to a conformational change in the autoinhibitory domain and remove it from the active site (doi:10.1016/j.jmb.2011.11.008).
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== Related health defects ==
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Calcineurin hyperactivation thought dysregulation of the Ca<sup>2+</sup> dynamic have been show to play a critical role in several diseases like Rheumatoid arthritis (RA), Schizophrenia ,Diabetes, Systemic Lupus Erythematosus as well as Alzheimer diseases (AD) <ref>http://www.uptodate.com/contents/pharmacology-of-cyclosporine-and-tacrolimus)</ref><ref>PMID: 12851457</ref><ref>PMID: 16988714</ref><ref>PMID:20421909</ref>.
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Taking the example of AD which is a age-related memory dysfunction, it it know that in older organism the brain is less plastic due to a dysregulation of Ca<sup>2+</sup> dynamic. This in addition to the presence of oligomeric Aß is sufficient to explain an enhancement of CaN activity leading to severals symptoms like decreased neurotransmission, synaptic loss and neuroinflammation<ref>PMID:22654726</ref>. Therefore calmodulin inhibitors are potential alternatives against Alzheimer diseases.
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It has been reported that Calcineurin activates the transcription factor [https://de.wikipedia.org/wiki/NF-AT NFAT] by forming a complex and dephosporylation (PMID:17502104). Following, the factor enters the nucleus and activates the expression of Interleukin-2.
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== Human/Rat calcineurin comparison ==
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[http://www.uniprot.org/uniprot/Q08209 Human] and [http://www.uniprot.org/uniprot/P63329 Rat] calcineurin have the same function and global structure [[Image:Human rat comparison.PNG|thumb|upright=4|left| Structure of rat calcineurin and human calcineurin]].
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The size (521 amino acids) and subunits of the linear structure are the same, as well as the 3D structure.
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<br style="clear:both" />
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[[Image:Proteopedia.PNG|thumb|upright=4|right| Structure of human calcineurin (up) and rat calcineurin (down) ]]
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<br style="clear:both" />
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However, there are a few differences, such as the secondary structures.
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For instance, Human Calcineurin has one Beta strand at <scene name='75/750223/Residues_11-13_beta_strand/1'>residues 11-13</scene> whereas Rat Calcineurin has not.
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== Binding Partners ==
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<br style="clear:both" />
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The main partners of interaction are [https://en.wikipedia.org/wiki/Calmodulin Calmodulin],NFATc1, NFATc2 and NFATc3.
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Indeed, Calcineurin is a highly conserved protein from yeast to mammals.
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Many of the calcineurin substrates’ contain a PxIxIT motif. Among them, beside the phosphorylated forms of NFAT we can also mentioned; cAMP response element binding protein (CREB), PP1, microtubule-associated protein tau and glycogen synthase kinase-3 beta (GSK- 3)(PMID: 17666045)(PMID: 22676853)(PMID: 14701880)(PMID: 7515479).
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<br style="clear:both" />
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Calcineurin is inhibited by the immunosuppressive drugs tacrolismus (FK506) or cyclosporine A (CsA). CsA and FK506 conduct their therapeutic role thought binding to the [https://en.wikipedia.org/wiki/Immunophilins immunophilins] cyclophilin and FK506 binding protein (FK506BP) respectively. The complexes CsA-cyclophilin and FK506-FK506BP bind then to calcineurin in a calcium-dependent manner thus inhibiting its phosphatase activity. Therefore the addition of these drugs to lymphocytes T prevent NFAT translocation to the nucleus and the subsequent activation its target gene.That's why FK506 and CsA are use in the treatment of various immune-mediated diseases. However since calcineurin is is widely expressed in non-haemopoietic tissues like the kidney and the hearth, both drugs present a long term toxicity and can lead to deleterious effect to these Organs (PMID: 8811062), (http://www.uptodate.com/contents/pharmacology-of-cyclosporine-and-tacrolimus).
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== Evolutionary conservation ==
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[[Image:Ih.jpg|thumb|upright=2|right|size=4| Evolutionary conservation of Calcineurin B within eukaryotes ]]
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'''Calcineurin A'''
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'''Cofactors''':
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This catalytic subunit is highly conserved. Nevertheless it can be up to 20 % larger in lower eukaryotic species.
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Calcineurin belong to the family of [https://en.wikipedia.org/wiki/Metalloprotein metalloprotein]. To conduct its activity it requires the presence of Fe3+ and Zn2+ ions in the active site (one per subunit).Superoxide dismutase has been shown to protect calcineurin from inactivation by preventing Fe3+ from oxidation. Thus after activation of calcineurin by calmodulin, the AID is displaced from the catalytic core exposing Fe3+ to oxidation (PMID: 8837775)(Calmodulin and Signal Transduction (p184), Linda J. Van Eldik,D. Martin Watterson (1998)).
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In addition, the NH<sub>2</sub> and COOH terminals are variable among species, as well as between calcineurin A genes within the same organism.
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The function of these variable domains is unknown.<ref name="paper">PMID: 11015619</ref>
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'''Calcineurin B'''
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This regulatory subunit is also highly conserved throughout evolution. For instance, the sequence of the rat calcineurin B brain isoform is exactly the same as the human calcineurin B.
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This high degree of conservation allows functional interchange of calcineurin B subunits between eukaryotic species. <ref name="paper" />
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<br style="clear:both" />
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== Calcineurin history ==
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Calcineurin was first detected by Wang and Desai in 1976 as a column fraction that inhibited the calmodulin-dependent cyclic nucleotide phosphodiesterase.
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Klee and Krinks did the first purification of calcineurin in 1978 and hypothesized that it might be a regulatory subunit of phosphodiesterase since it was demonstrated to inhibit phosphodiesterase activity.
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== Related health defects ==
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Klee et al. named it “calcineurin” on the basis of its Ca<sup>2+</sup>-binding properties (calci) and localization to neuronal tissue (neurin).
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Calcineurin hyperactivation thought dysregulation of the Ca2+ dynamic have been show to play a critical role in several diseases like Rheumatoid arthritis (RA), Schizophrenia ,Diabetes, Systemic Lupus Erythematosus as well as Alzheimer diseases (http://www.uptodate.com/contents/pharmacology-of-cyclosporine-and-tacrolimus)(PMID: 12851457)(PMID: 16988714)(PMID: 20421909)(PMID: 22654726).In order to fight those health defects calmodulin inhibitors can be administrated.
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From this time, functions and structure of Calcineurin have been discovered as well as medical applications (e.g. calcineurin inhibitors). <ref name="paper" />
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== References ==
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<references/>

Current revision

Rat Calcineurin

PDB ID 4il1

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Proteopedia Page Contributors and Editors (what is this?)

Camille Zumstein

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