User:Camille Zumstein/Sandbox

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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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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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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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== 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.
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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 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>.
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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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<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>.
'''Cofactors''':
'''Cofactors''':
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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 <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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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>.
== 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) <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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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 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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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.
== 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=4|left| Structure of rat calcineurin and human calcineurin ]].
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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.
The size (521 amino acids) and subunits of the linear structure are the same, as well as the 3D structure.
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[[Image:Proteopedia.PNG|thumb|upright=4|right| Structure of human calcineurin (up) and rat calcineurin (down) ]] However, there are a few differences, such as the secondary structures.
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[[Image:Proteopedia.PNG|thumb|upright=4|right| Structure of human calcineurin (up) and rat calcineurin (down) ]]
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However, there are a few differences, such as the secondary structures.
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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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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