Group:MUZIC:Calcineurin
From Proteopedia
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== Calcineurin in the muscle cells == | == Calcineurin in the muscle cells == | ||
| + | This calcium/calmodulin-dependent protein serine/threonine phosphate is localised in the nucleus and in the Z-disc of muscle fibres. Its activity is controlled by calcium signals that lead to remodelling of skeletal and cardiac muscle in response to physiological and pathological stimuli. | ||
| + | It has been shown that at least part of the cardiomyocyte calcineurin pool localises to the z-disc, where it resides in close proximity to several important modulators of its activity, being among those the calsarcins protein family. <ref> PMID: 21257757</ref> | ||
| - | + | == Calcineurin interactions in the Z-disc and their physiological role == | |
| - | + | The Z-disc is a macromolecular assembly of proteins in the boundaries of sarcomeres that 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. | |
| - | + | ||
| - | + | ||
| + | Z-disc proteins interacting with Calcineurin can be classified in two categories: Positive modulators and negative modulators, accordingly with their capacity to activate or deactivate the Calcineurin phosphatase activity. | ||
Revision as of 12:17, 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 muscle cells
This calcium/calmodulin-dependent protein serine/threonine phosphate is localised in the nucleus and in the Z-disc of muscle fibres. Its activity is controlled by calcium signals that lead to remodelling of skeletal and cardiac muscle in response to physiological and pathological stimuli. It has been shown that at least part of the cardiomyocyte calcineurin pool localises to the z-disc, where it resides in close proximity to several important modulators of its activity, being among those the calsarcins protein family. [6]
Calcineurin interactions in the Z-disc and their physiological role
The Z-disc is a macromolecular assembly of proteins in the boundaries of sarcomeres that 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.
Z-disc proteins interacting with Calcineurin can be classified in two categories: Positive modulators and negative modulators, accordingly with their capacity to activate or deactivate the Calcineurin phosphatase activity.
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
