Group:MUZIC:Calcineurin
From Proteopedia
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On the other hand, CnB is a 168 polipeptide chain that belongs to the EF-hand calcium binding protein family. this subunit is composed of two lobes with two calcium ions bound by <scene name='User:Ariadna_Rodriguez-Chamorro/Workbench/Calcineurin/Cnb_ef-hand/2'>EF-hand motifs</scene> in each lobe. <ref> PMID: 8524402</ref> | On the other hand, CnB is a 168 polipeptide chain that belongs to the EF-hand calcium binding protein family. this subunit is composed of two lobes with two calcium ions bound by <scene name='User:Ariadna_Rodriguez-Chamorro/Workbench/Calcineurin/Cnb_ef-hand/2'>EF-hand motifs</scene> in each lobe. <ref> PMID: 8524402</ref> | ||
| - | == Calcineurin in the Z-disc, its interactions their physiological role == | + | == Calcineurin in the Z-disc, its interactions and their physiological role == |
The Z-disc is a macromolecular assembly of proteins in the boundaries of sarcomeres of muscle cells. For many years it was seen as a region where the F-actin filaments where cross-linked. Nevertheless, in the last 10 years this picture has been changing and it has been shown to be a dynamic macromolecular assembly where protein functions are modulated in response to different stimuli. Calcineurin is one of those proteins that resides in the Z-disc and which phosphatase activity is modulated by its interacting partners. The calcium/calmodulin-dependent phosphatase calcineurin plays a central role in cardiomyocyte signal integration by activating NFAT through dephosphorylation and thereby activating the cell remodelling program. As it has been shown by Frey and collaborators in 2004, the up-regulation of calcineurin phosphatase activity in mouse cardiomyocyte led to pathological cardiac hypertrophy. <ref> PMID: 21257757</ref> | The Z-disc is a macromolecular assembly of proteins in the boundaries of sarcomeres of muscle cells. For many years it was seen as a region where the F-actin filaments where cross-linked. Nevertheless, in the last 10 years this picture has been changing and it has been shown to be a dynamic macromolecular assembly where protein functions are modulated in response to different stimuli. Calcineurin is one of those proteins that resides in the Z-disc and which phosphatase activity is modulated by its interacting partners. The calcium/calmodulin-dependent phosphatase calcineurin plays a central role in cardiomyocyte signal integration by activating NFAT through dephosphorylation and thereby activating the cell remodelling program. As it has been shown by Frey and collaborators in 2004, the up-regulation of calcineurin phosphatase activity in mouse cardiomyocyte led to pathological cardiac hypertrophy. <ref> PMID: 21257757</ref> | ||
| - | Z-disc proteins interacting with calcineurin can be classified in two categories: Positive modulators and negative modulators, accordingly with their ability to activate or deactivate the calcineurin phosphatase activity. Calsarcin-1(FATZ-2/myozenin-2) is a negative modulator of calcineurin and it has been shown that this interaction plays an important role in the cell response to pressure overload.<ref>PMID: 15543153</ref> Another Z-disc negative modulator is PICOT(protein kinase C-interacting cousin of thioredoxin). PICOT displaces calcineurin from the Z-disc preventing the activation by other partners. <ref>PMID: 18258855 </ref> As positive modulator it has been described Lmcd1/Dyxin, which up-regulation caused hypertrophy accompanied by strong activation of calcineurin signalling. <ref>PMID: 20600098</ref> | ||
| + | Z-disc proteins interacting with calcineurin can be classified in two categories: Positive modulators and negative modulators, accordingly with their ability to activate or deactivate the calcineurin phosphatase activity. Calsarcin-1(FATZ-2/myozenin-2) is a negative modulator of calcineurin and it has been shown that this interaction plays an important role in the cell response to pressure overload.<ref>PMID: 15543153</ref> Another Z-disc negative modulator is PICOT(protein kinase C-interacting cousin of thioredoxin). PICOT displaces calcineurin from the Z-disc preventing the activation by other partners. <ref>PMID: 18258855 </ref> As positive modulator it has been described Lmcd1/Dyxin, which up-regulation caused hypertrophy accompanied by strong activation of calcineurin signalling. <ref>PMID: 20600098</ref> | ||
== Further Readings == | == Further Readings == | ||
Revision as of 17:50, 3 July 2011
Contents |
Calcineurin
Calcineurin is a calcium calmoduline dependent phosphatase present in many different type of cells. This phosphatase has been described to be mainly localized in the cyoplasma where dephosphorylates members of the nuclear factor of activated T-cell (NFAT) family of transcription factors. As a result NFAT is translocated to the nuclei and activates target genes that promote cell proliferation.[1]
Structure
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The calcium/calmodulin-dependent phosphatase calcineurin is composed by two chains: chain A, (CnA) which is the catalytic subunit and chain B(CnB) confers calcium sensitivity. [2]Those two subunits are tighlty bound and they only disociate under denaturant conditions.[3] The interaction between CnB and CnA is essential for the phosphatase activity of Calcineurin and while it is known that calcium binding to CnB promotes the interaction CnB with CnA, the mechanism whereby it goes is not yet fully understood. [4]
CnA contains a followed by an alpha-helical region which forms the and an Calmodulin-binding region. In the C-terminal region of CnA there are 18 residues considered as an that lies over the substrate binding cleft in the catalytic domain. On the other hand, CnB is a 168 polipeptide chain that belongs to the EF-hand calcium binding protein family. this subunit is composed of two lobes with two calcium ions bound by in each lobe. [5]
Calcineurin in the Z-disc, its interactions and their physiological role
The Z-disc is a macromolecular assembly of proteins in the boundaries of sarcomeres of muscle cells. For many years it was seen as a region where the F-actin filaments where cross-linked. Nevertheless, in the last 10 years this picture has been changing and it has been shown to be a dynamic macromolecular assembly where protein functions are modulated in response to different stimuli. Calcineurin is one of those proteins that resides in the Z-disc and which phosphatase activity is modulated by its interacting partners. The calcium/calmodulin-dependent phosphatase calcineurin plays a central role in cardiomyocyte signal integration by activating NFAT through dephosphorylation and thereby activating the cell remodelling program. As it has been shown by Frey and collaborators in 2004, the up-regulation of calcineurin phosphatase activity in mouse cardiomyocyte led to pathological cardiac hypertrophy. [6]
Z-disc proteins interacting with calcineurin can be classified in two categories: Positive modulators and negative modulators, accordingly with their ability to activate or deactivate the calcineurin phosphatase activity. Calsarcin-1(FATZ-2/myozenin-2) is a negative modulator of calcineurin and it has been shown that this interaction plays an important role in the cell response to pressure overload.[7] Another Z-disc negative modulator is PICOT(protein kinase C-interacting cousin of thioredoxin). PICOT displaces calcineurin from the Z-disc preventing the activation by other partners. [8] As positive modulator it has been described Lmcd1/Dyxin, which up-regulation caused hypertrophy accompanied by strong activation of calcineurin signalling. [9]
Further Readings
References
- ↑ Rao A, Luo C, Hogan PG. Transcription factors of the NFAT family: regulation and function. Annu Rev Immunol. 1997;15:707-47. PMID:9143705 doi:10.1146/annurev.immunol.15.1.707
- ↑ Kissinger CR, Parge HE, Knighton DR, Lewis CT, Pelletier LA, Tempczyk A, Kalish VJ, Tucker KD, Showalter RE, Moomaw EW, et al.. Crystal structures of human calcineurin and the human FKBP12-FK506-calcineurin complex. Nature. 1995 Dec 7;378(6557):641-4. PMID:8524402 doi:http://dx.doi.org/10.1038/378641a0
- ↑ Kissinger CR, Parge HE, Knighton DR, Lewis CT, Pelletier LA, Tempczyk A, Kalish VJ, Tucker KD, Showalter RE, Moomaw EW, et al.. Crystal structures of human calcineurin and the human FKBP12-FK506-calcineurin complex. Nature. 1995 Dec 7;378(6557):641-4. PMID:8524402 doi:http://dx.doi.org/10.1038/378641a0
- ↑ Stemmer PM, Klee CB. Dual calcium ion regulation of calcineurin by calmodulin and calcineurin B. Biochemistry. 1994 Jun 7;33(22):6859-66. PMID:8204620
- ↑ Kissinger CR, Parge HE, Knighton DR, Lewis CT, Pelletier LA, Tempczyk A, Kalish VJ, Tucker KD, Showalter RE, Moomaw EW, et al.. Crystal structures of human calcineurin and the human FKBP12-FK506-calcineurin complex. Nature. 1995 Dec 7;378(6557):641-4. PMID:8524402 doi:http://dx.doi.org/10.1038/378641a0
- ↑ Frank D, Frey N. Cardiac Z-disc signaling network. J Biol Chem. 2011 Mar 25;286(12):9897-904. Epub 2011 Jan 21. PMID:21257757 doi:10.1074/jbc.R110.174268
- ↑ Frey N, Barrientos T, Shelton JM, Frank D, Rutten H, Gehring D, Kuhn C, Lutz M, Rothermel B, Bassel-Duby R, Richardson JA, Katus HA, Hill JA, Olson EN. Mice lacking calsarcin-1 are sensitized to calcineurin signaling and show accelerated cardiomyopathy in response to pathological biomechanical stress. Nat Med. 2004 Dec;10(12):1336-43. Epub 2004 Nov 14. PMID:15543153 doi:nm1132
- ↑ Jeong D, Kim JM, Cha H, Oh JG, Park J, Yun SH, Ju ES, Jeon ES, Hajjar RJ, Park WJ. PICOT attenuates cardiac hypertrophy by disrupting calcineurin-NFAT signaling. Circ Res. 2008 Mar 28;102(6):711-9. Epub 2008 Feb 7. PMID:18258855 doi:10.1161/CIRCRESAHA.107.165985
- ↑ Frank D, Frauen R, Hanselmann C, Kuhn C, Will R, Gantenberg J, Fuzesi L, Katus HA, Frey N. Lmcd1/Dyxin, a novel Z-disc associated LIM protein, mediates cardiac hypertrophy in vitro and in vivo. J Mol Cell Cardiol. 2010 Oct;49(4):673-82. Epub 2010 Jun 30. PMID:20600098 doi:10.1016/j.yjmcc.2010.06.009
