User:Camille Zumstein/Sandbox
From Proteopedia
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==Structure Rat Calcineurin== | ==Structure Rat Calcineurin== | ||
| - | <StructureSection load='4il1' size='340' side='right' caption=' | + | <StructureSection load='4il1' size='340' side='right' caption='' scene=''> |
| - | <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](CaM) in a calcium-dependant manner. Calcineurin is the only known calmodulin-activated protein phosphatase. Calcineurin is responsible mainly for dephosphorylating several members of the [https://en.wikipedia.org/wiki/NFAT NFAT] transcription factor family (including NFATc1 through NFATc4). | + | <scene name='75/750223/Picture_intro/1'> Calcineurin each of the four chains of the monomer is shown in a different color, spheres represent calcium ions. </scene> is a serine/threonine phosphatase that is activated by [https://en.wikipedia.org/wiki/Calmodulin calmodulin](CaM) in a calcium-dependant manner. Calcineurin is the only known calmodulin-activated protein phosphatase. Calcineurin is responsible mainly for dephosphorylating several members of the [https://en.wikipedia.org/wiki/NFAT NFAT] transcription factor family (including NFATc1 through NFATc4). |
''' Localisation and expression''': | ''' Localisation and expression''': | ||
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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>. | 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</scene> is inhibited by the immunosuppressive drugs tacrolismus (FK506) or cyclosporine A (CsA). CsA and <scene name='75/750223/Fk506/1'>FK506</scene> 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</scene> is inhibited by the immunosuppressive drugs tacrolismus (FK506) or cyclosporine A (CsA). CsA and <scene name='75/750223/Fk506/1'>FK506</scene> 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 catalytic core 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 catalytic core 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 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> | + | 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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| - | Therefore calmodulin inhibitors are potential alternatives against Alzheimer diseases. | + | |
== Human/Rat calcineurin comparison == | == Human/Rat calcineurin comparison == | ||
Revision as of 18:01, 23 January 2017
Structure Rat Calcineurin
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