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==Rat Calcineurin==
==Rat Calcineurin==
<StructureSection load='4il1' size='340' side='right' caption='' scene=''>
<StructureSection load='4il1' size='340' side='right' caption='' scene=''>
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== Function ==
== Function ==
<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.
<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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'''Secondary structure:'''
'''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]]]
[[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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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" />
<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]].
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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<br style="clear:both" />
<br style="clear:both" />
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== Principle of action ==
== Principle of action ==
[[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>]]
[[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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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.
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" />
<br style="clear:both" />
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== Binding Partners ==
== Binding Partners ==
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The main partners of interaction are [https://en.wikipedia.org/wiki/Calmodulin Calmodulin],NFATc1, NFATc2 and NFATc3.
The main partners of interaction are [https://en.wikipedia.org/wiki/Calmodulin Calmodulin],NFATc1, NFATc2 and NFATc3.
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)<ref>PMID: 17666045</ref><ref>PMID: 22676853</ref><ref>PMID:14701880</ref><ref>PMID: 7515479</ref>.
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)<ref>PMID: 17666045</ref><ref>PMID: 22676853</ref><ref>PMID:14701880</ref><ref>PMID: 7515479</ref>.
<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>, (http://www.uptodate.com/contents/pharmacology-of-cyclosporine-and-tacrolimus).
<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>, (http://www.uptodate.com/contents/pharmacology-of-cyclosporine-and-tacrolimus).
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'''Cofactors''':
'''Cofactors''':
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 <scene name='75/750223/Catalytic_core/1'> catalytic core,with phosphate and Fe and Zn ions bound </scene> exposing Fe3+ to oxidation <ref>PMID: 8837775</ref>(Calmodulin and Signal Transduction (p184), Linda J. Van Eldik,D. Martin Watterson (1998)).
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 <scene name='75/750223/Catalytic_core/1'> catalytic core,with phosphate and Fe and Zn ions bound </scene> exposing Fe3+ to oxidation <ref>PMID: 8837775</ref>(Calmodulin and Signal Transduction (p184), Linda J. Van Eldik,D. Martin Watterson (1998)).
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== Related health defects ==
== Related health defects ==
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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(AD) (http://www.uptodate.com/contents/pharmacology-of-cyclosporine-and-tacrolimus)<ref>PMID: 12851457</ref><ref>PMID: 16988714</ref><ref>PMID:20421909</ref>.
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(AD) (http://www.uptodate.com/contents/pharmacology-of-cyclosporine-and-tacrolimus)<ref>PMID: 12851457</ref><ref>PMID: 16988714</ref><ref>PMID:20421909</ref>.
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 Ca2+ 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 , neuroinflammation ...<ref>PMID: 22654726</ref>Therefore calmodulin inhibitors are potential alternatives against Alzheimer diseases.
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 Ca2+ 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 , neuroinflammation ...<ref>PMID: 22654726</ref>Therefore calmodulin inhibitors are potential alternatives against Alzheimer diseases.
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== Human/Rat calcineurin comparison ==
== 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=2|right| Structure of rat calcineurin and human calcineurin ]].
[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=2|right| Structure of rat calcineurin and human calcineurin ]].
The size (521 amino acids) and subunits of the linear structure are the same, as well as the 3D structure.
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" />
<br style="clear:both" />
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However, there are a few differences, such as the secondary structures. [[Image:Proteopedia.PNG|thumb|upright=2|right|size=4| Structure of human calcineurin (up) and rat calcineurin (down) ]]
However, there are a few differences, such as the secondary structures. [[Image:Proteopedia.PNG|thumb|upright=2|right|size=4| Structure of human calcineurin (up) and rat calcineurin (down) ]]
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.
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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Indeed, Calcineurin is a highly conserved protein from yeast to mammals.
Indeed, Calcineurin is a highly conserved protein from yeast to mammals.
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== Evolutionary conservation ==
== Evolutionary conservation ==
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'''Calcineurin A'''
'''Calcineurin A'''
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This catalytic subunit is highly conserved. Nevertheless it can be up to 20% larger in lower eukaryotic species.
This catalytic subunit is highly conserved. Nevertheless it can be up to 20% larger in lower eukaryotic species.
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In addition, the NH2 and COOH terminals are variable among species, as well as between calcineurin A genes within the same organism.
In addition, the NH2 and COOH terminals are variable among species, as well as between calcineurin A genes within the same organism.
The function of these variable domains is unknown.<ref name="paper">PMID: 11015619</ref>
The function of these variable domains is unknown.<ref name="paper">PMID: 11015619</ref>
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'''Calcineurin B'''
'''Calcineurin B'''
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[[Image:Ih.jpg|thumb|upright=2|right|size=4| Evolutionary conservation within eukaryotes ]]
[[Image:Ih.jpg|thumb|upright=2|right|size=4| Evolutionary conservation within eukaryotes ]]
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.
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.
This high degree of conservation allows functional interchange of calcineurin B subunits between eukaryotic species. <ref name="paper" />
This high degree of conservation allows functional interchange of calcineurin B subunits between eukaryotic species. <ref name="paper" />
<br style="clear:both" />
<br style="clear:both" />
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== Calcineurin history ==
== 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.
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.
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.
Klee et al. named it “calcineurin” on the basis of its Ca2+-binding properties (calci) and localization to neuronal tissue (neurin).
Klee et al. named it “calcineurin” on the basis of its Ca2+-binding properties (calci) and localization to neuronal tissue (neurin).
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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" />
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 ==
== References ==
<references/>
<references/>

Revision as of 11:59, 27 January 2017

Rat Calcineurin

Rat Calcineurin

PDB ID 4il1

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Camille Zumstein

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