Group:MUZIC:Calcineurin

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== Introduction ==
== Introduction ==
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Calcineurin, a serine-threonine phosphatase also known as protein phosphatase 2B (PP2B), is a heterodimeric protein composed of a catalytic subunit, with phosphatase activity, and a regulatory subunit, Ca2+ regulated. Calcineurin is located in the cytoplasm, where sustained low-amplitude Ca2+ waves trigger its phosphatase activity <ref>PMID:9126747</ref>. Calcineurin’s substrates are different members of the nuclear factor activated T-cells (NFAT) transcription factor family, which are dephosphorylated, and consequently, translocate to the nucleus for activating the expression of different gene networks.<ref>PMID: 9143705</ref>. The presence of Calcineurin in different cell types and organisms, ranging from T-lymphocytes to skeletal muscle, and from yeast to humans, highlights its important role signaling pathways controlling biological responses to environmental stimulus.
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Calcineurin, a serine-threonine phosphatase also known as protein phosphatase 2B (PP2B), is a heterodimeric protein composed of a catalytic subunit, with phosphatase activity, and a regulatory subunit, Ca2+ regulated. Calcineurin is located in the cytoplasm, where sustained low-amplitude Ca2+ waves trigger its phosphatase activity <ref>PMID:9126747</ref>. Calcineurin’s substrates are different members of the nuclear factor activated T-cells (NFAT) transcription factor family, which are dephosphorylated, and consequently, translocate to the nucleus for activating expression of different gene networks.<ref>PMID: 9143705</ref>. The presence of Calcineurin in different cell types and organisms, ranging from T-lymphocytes to skeletal muscle, and from yeast to humans, highlights its important role signaling pathways controlling biological responses to environmental stimulus.
==Sequence Annotation==
==Sequence Annotation==

Revision as of 13:54, 5 February 2013

Contents

Introduction

Calcineurin, a serine-threonine phosphatase also known as protein phosphatase 2B (PP2B), is a heterodimeric protein composed of a catalytic subunit, with phosphatase activity, and a regulatory subunit, Ca2+ regulated. Calcineurin is located in the cytoplasm, where sustained low-amplitude Ca2+ waves trigger its phosphatase activity [1]. Calcineurin’s substrates are different members of the nuclear factor activated T-cells (NFAT) transcription factor family, which are dephosphorylated, and consequently, translocate to the nucleus for activating expression of different gene networks.[2]. The presence of Calcineurin in different cell types and organisms, ranging from T-lymphocytes to skeletal muscle, and from yeast to humans, highlights its important role signaling pathways controlling biological responses to environmental stimulus.

Sequence Annotation

The heterodimeric Calcineurin is composed of two subunits: the serine/threonine-protein phosphatase 2B catalytic subunit alpha isoform chain A (CnA), and the Calcineurin subunit B type 1 (CnB) [3]. Each of the subunits has alternative names in the literature, as it is shown in their uniprotKB entries Q08209 and P63098. CnA comprises a globular catalytic domain (residues 1 to 301), a CnB binding region (residues 247 to 253 and 296 to 301), a calmodulin-binding region (residues 392 to 414), and an autoinhibitory peptide (residues 465 to 487). CnB is composed of four EF hands spanning from residue 18 to 163 [4].

Structure

The structure was solved by macromolecular crystallography at a resolution of 2.1 Å. 1AUI

Drag the structure with the mouse to rotate

CnA contains a followed by an alpha-helical region, forming the . It also has a calmodulin-binding region, which is critical for Calcineurin's catalytic activity. In the C-terminal region of CnA there are 18 residues considered an , because it blocks the substrate binding cleft on the catalytic domain. The CnB is a 168 polipeptide chain, belonging 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].

Function and Interactions

Calcineurin is specifically activated by low-amplitude Ca2+ waves [6], which promotes association of Calmodulin with CnA and a conformational change of CnB, resulting in activation of the phosphatase catalytic domain. Different isoforms of the NFAT transcription factors are Calcineurin substrates, which after dephosphorylation translocate from the cytoplasm to the nucleus, finding their different target genes [7].

In T-lymphocytes, Calcineurin controls the response to foreign antigens via NFAT, which activated gene expression networks determine T-cell response to the external stimulus. Such response can be inhibited by cyclosporin A (CsA) and FK-506, calcineurin inhibitors, used to immunosuppress organ rejection in human transplants [8].

The Calcineurin/NFAT signaling pathway determines the fiber type composition of skeletal muscle in response to motor neuron activity. Dephosphorylation of isoform NFTAc1 activates expression of the slow myosin heavy chain (MyHC), and other slow fiber type specific genes; therefore, determining the slow fiber type composition of skeletal muscle [9]. This was experimentally confirmed in regenerating and adult muscles by using VIVIT, a blocker of the interaction between Calcineurin and NFATc1, which inhibited the activation of MyHC-slow promoter. Additionally, it was possible to rescue the slow fiber phenotype by a constitutively active form of NFAT, demonstrating that the slow gene activation program is controlled by the Calcineurin/NFAT signaling pathway [10]. Different experiments suggest that Calcineurin also controls the slow fiber type composition via MEF-2, another family of transcription factors which appears during early stages of myocytes differentiation and activate the expression of proteins associated with oxidative metabolism. It was shown that the treatment with CsA blocked the response of MEF-2 to exercise stimulus, that over-expression of Calcineurin increases dramatically the activity of MEF-2, and that the activation of both Calcineurin and MEF-2 pathways promotes expression of myoglobin, myosin heavy chain, and slow troponin I [11]. Consequently, Calcineurin can control the slow fiber type phenotype by MEF-2 signaling pathway. Likewise, it is open the question of whether there is cross-talking with other pathways.

Calcineurin interacts with the protein family FATZ (also known as Calsarcins or Myozenins), which is composed by three isoforms. The isoform FATZ-1 (Calsarcin-2 and Myozenin-1) is a negative regulator of Calcineurin/NFAT signaling pathway in fast-twitch fibers. In absence of FATZ-1 the activity of the Calcineurin/NFAT signaling pathway increases, consequently, there are a major number of oxidative fibers, and less fatigue of FATZ-1 mutant compared to FATZ-1 wild type mice subjected to long endurance exercise. These findings support that the interaction between FATZ-1 and Calcineurin is another check point in the signaling pathways controlling skeletal muscle fiber type composition and response to exercise performance [12].

Besides controlling fiber type composition, the Calcineurin/NFAT signaling pathway controls the hypertrophic response in striated muscle. In cardiomyocytes, it is considered a mechano-sensorial signaling pathway controlling the cell proliferation response to pressure overload. The dephosphorylation of NFATc4, and cooperation with GATA4 and MEF-2, activates the hypertrophic gene program [13]. Cardiomyocytes exposed to hypertrophic agonists and treated with CsA, FK-506, and Cabin/cain prevents the development of hypertrophy. Additionally, Calcineurin activity is controlled in response to pressure overload by interaction with the Z-disc protein FATZ-2 (calsarcin-1/Myozenin-2), which is a negative regulator in cardiomyocytes and leads to hypertrophic response in FATZ-2 deficient mice subjected to hypertrophic agonists [14]. Other Z-disc proteins interact with Calcineurin and regulated its activity. The interaction with MLP suggests that anchoring Calcineurin to the Z-disc is important in controlling its activity, therefore, the cell response to mechanical signals [15]. Another protein, PICOT, displaces calcineurin from the Z-disc preventing the activation by other partners. [16] As positive modulator it has been described Lmcd1/Dyxin, which up-regulation caused hypertrophy accompanied by strong activation of calcineurin signaling [17].

Calcineurin has been also implicated in hypertrophy driven by insulin growth factor (IGFs), which are known to stimulate muscle hypertrophy in skeletal muscle. Experimental data showed that treatment of muscle cultured cells with IGFs up-regulates the transcriptional levels of CnA, promotes association between NFATc1 and GATA-2, which isoforms in heart control the hypertrophic response, and displays phenotypic characteristics of cellular hypertrophy. In support to these findings it was seen that treatment with CsA, prevented the activation of the hypertrophic program [18]. Other experiments showed that muscle hypertrophy is not only driven by the Calcineurin/NFAT pathway, given that constitutive expression of Calcineurin is not enough to induce hypertrophy [19], suggesting that other signaling pathways may be responsible for muscle hypertrophy in response to IGFs.

Pathology

It is well established in animal models that over activation of the Calcineurin/NFAT pathway leads to cardiac hypertrophy [20], [21]. However, the treatment of organ transplant patients with Calcineurin inhibitors can lead to a human hypertrophic cardiomyopathy phenotype, being reversible upon discontinuation [22]. Furthermore, there is controversy about whether the Calcineurin enzymatic activity is increased or not in biopsies from hypertrophic and failing human hearts [23]. In consequence, despite being a crucial signaling pathway controlling the hypertrophic response in cardiomyocytes, the role of Calcineurin in human hypertrophic cardiomyopathy remains unclear.

Further Readings

Structure of calcineurin

1: Majava V, Kursula P. Domain swapping and different oligomeric States for the complex between calmodulin and the calmodulin-binding domain of calcineurin a. PLoS One. 2009;4(4):e5402. Epub 2009 Apr 30. PubMed PMID: 19404396; PubMed Central PMCID: PMC2671406.

2: Ye Q, Wang H, Zheng J, Wei Q, Jia Z. The complex structure of calmodulin bound to a calcineurin peptide. Proteins. 2008 Oct;73(1):19-27. PubMed PMID: 18384083.

3: Li H, Zhang L, Rao A, Harrison SC, Hogan PG. Structure of calcineurin in complex with PVIVIT peptide: portrait of a low-affinity signalling interaction. J Mol Biol. 2007 Jun 22;369(5):1296-306. Epub 2007 Apr 19. PubMed PMID: 17498738.

4: Huai Q, Kim HY, Liu Y, Zhao Y, Mondragon A, Liu JO, Ke H. Crystal structure of calcineurin-cyclophilin-cyclosporin shows common but distinct recognition of immunophilin-drug complexes. Proc Natl Acad Sci U S A. 2002 Sep 17;99(19):12037-42. Epub 2002 Sep 6. PubMed PMID: 12218175; PubMed Central PMCID: PMC129394.

5: Jin L, Harrison SC. Crystal structure of human calcineurin complexed with cyclosporin A and human cyclophilin. Proc Natl Acad Sci U S A. 2002 Oct 15;99(21):13522-6. Epub 2002 Sep 30. PubMed PMID: 12357034; PubMed Central PMCID: PMC129706.


Calcineurin and Hyperthrophic cardiomyopathy

1: Molkentin JD. Calcineurin-NFAT signaling regulates the cardiac hypertrophic response in coordination with the MAPKs. Cardiovasc Res. 2004 Aug 15;63(3):467-75. Review. PubMed PMID: 15276472.

2: Rothermel BA, Vega RB, Williams RS. The role of modulatory calcineurin-interacting proteins in calcineurin signaling. Trends Cardiovasc Med. 2003 Jan;13(1):15-21. Review. PubMed PMID: 12554096.

3: Molkentin JD. Calcineurin and beyond: cardiac hypertrophic signaling. Circ Res. 2000 Oct 27;87(9):731-8. Review. PubMed PMID: 11055975.

4: Frank D, Frey N. Cardiac Z-disc signaling network. J Biol Chem. 2011 Mar 25;286(12):9897-904. Epub 2011 Jan 21. Review. PubMed PMID: 21257757; PubMed Central PMCID: PMC3060542.

Calcineurin on the Z-disc

1: Frank D, Frauen R, Hanselmann C, Kuhn C, Will R, Gantenberg J, Füzesi 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. PubMed PMID: 20600098.

2: Frey N, Frank D, Lippl S, Kuhn C, Kögler H, Barrientos T, Rohr C, Will R, Müller OJ, Weiler H, Bassel-Duby R, Katus HA, Olson EN. Calsarcin-2 deficiency increases exercise capacity in mice through calcineurin/NFAT activation. J Clin Invest. 2008 Nov;118(11):3598-608. Epub 2008 Oct 9. PubMed PMID: 18846255; PubMed Central PMCID: PMC2564612.

3: 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. PubMed PMID: 18258855.

4: Frank D, Kuhn C, van Eickels M, Gehring D, Hanselmann C, Lippl S, Will R, Katus HA, Frey N. Calsarcin-1 protects against angiotensin-II induced cardiac hypertrophy. Circulation. 2007 Nov 27;116(22):2587-96. Epub 2007 Nov 19. Erratum in: Circulation. 2008 Jan 22;117(3):e19. PubMed PMID: 18025526.

5: Faul C, Dhume A, Schecter AD, Mundel P. Protein kinase A, Ca2+/calmodulin-dependent kinase II, and calcineurin regulate the intracellular trafficking of myopodin between the Z-disc and the nucleus of cardiac myocytes. Mol Cell Biol. 2007 Dec;27(23):8215-27. Epub 2007 Oct 8. PubMed PMID: 17923693; PubMed Central PMCID: PMC2169179.

6: Heineke J, Ruetten H, Willenbockel C, Gross SC, Naguib M, Schaefer A, Kempf T, Hilfiker-Kleiner D, Caroni P, Kraft T, Kaiser RA, Molkentin JD, Drexler H, Wollert KC. Attenuation of cardiac remodeling after myocardial infarction by muscle LIM protein-calcineurin signaling at the sarcomeric Z-disc. Proc Natl Acad Sci U S A. 2005 Feb 1;102(5):1655-60. Epub 2005 Jan 21. PubMed PMID: 15665106; PubMed Central PMCID: PMC547821.

7: Hayashi T, Arimura T, Itoh-Satoh M, Ueda K, Hohda S, Inagaki N, Takahashi M, Hori H, Yasunami M, Nishi H, Koga Y, Nakamura H, Matsuzaki M, Choi BY, Bae SW, You CW, Han KH, Park JE, Knöll R, Hoshijima M, Chien KR, Kimura A. Tcap gene mutations in hypertrophic cardiomyopathy and dilated cardiomyopathy. J Am Coll Cardiol. 2004 Dec 7;44(11):2192-201. PubMed PMID: 15582318.

8: Frey N, Barrientos T, Shelton JM, Frank D, Rütten 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. PubMed PMID: 15543153.

9: Li HH, Kedar V, Zhang C, McDonough H, Arya R, Wang DZ, Patterson C. Atrogin-1/muscle atrophy F-box inhibits calcineurin-dependent cardiac hypertrophy by participating in an SCF ubiquitin ligase complex. J Clin Invest. 2004 Oct;114(8):1058-71. PubMed PMID: 15489953; PubMed Central PMCID: PMC522252.

10: Frey N, Olson EN. Calsarcin-3, a novel skeletal muscle-specific member of the calsarcin family, interacts with multiple Z-disc proteins. J Biol Chem. 2002 Apr 19;277(16):13998-4004. Epub 2002 Feb 12. PubMed PMID: 11842093.

References

  1. ↑ Dolmetsch RE, Lewis RS, Goodnow CC, Healy JI. Differential activation of transcription factors induced by Ca2+ response amplitude and duration. Nature. 1997 Apr 24;386(6627):855-8. PMID:9126747 doi:10.1038/386855a0
  2. ↑ 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
  3. ↑ 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
  4. ↑ Guerini D. Calcineurin: not just a simple protein phosphatase. Biochem Biophys Res Commun. 1997 Jun 18;235(2):271-5. PMID:9199180 doi:10.1006/bbrc.1997.6802
  5. ↑ 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
  6. ↑ Dolmetsch RE, Lewis RS, Goodnow CC, Healy JI. Differential activation of transcription factors induced by Ca2+ response amplitude and duration. Nature. 1997 Apr 24;386(6627):855-8. PMID:9126747 doi:10.1038/386855a0
  7. ↑ Guerini D. Calcineurin: not just a simple protein phosphatase. Biochem Biophys Res Commun. 1997 Jun 18;235(2):271-5. PMID:9199180 doi:10.1006/bbrc.1997.6802
  8. ↑ Crabtree GR. Generic signals and specific outcomes: signaling through Ca2+, calcineurin, and NF-AT. Cell. 1999 Mar 5;96(5):611-4. PMID:10089876
  9. ↑ Schiaffino S. Fibre types in skeletal muscle: a personal account. Acta Physiol (Oxf). 2010 Aug;199(4):451-63. doi:, 10.1111/j.1748-1716.2010.02130.x. Epub 2010 Mar 26. PMID:20353491 doi:10.1111/j.1748-1716.2010.02130.x
  10. ↑ Dieminger L, Schultz DR, Arnold PI. Activation of the classical complement pathway in human serum by a small oligosaccharide. J Immunol. 1979 Nov;123(5):2201-11. PMID:489979
  11. ↑ Bassel-Duby R, Olson EN. Signaling pathways in skeletal muscle remodeling. Annu Rev Biochem. 2006;75:19-37. PMID:16756483 doi:10.1146/annurev.biochem.75.103004.142622
  12. ↑ Conlon KC, Bading JR, DiResta GR, Corbally MT, Gelbard AS, Brennan MF. Validation of transport measurements in skeletal muscle with N-13 amino acids using a rabbit isolated hindlimb model. Life Sci. 1989;44(13):847-59. PMID:2564612
  13. ↑ Molkentin JD, Lu JR, Antos CL, Markham B, Richardson J, Robbins J, Grant SR, Olson EN. A calcineurin-dependent transcriptional pathway for cardiac hypertrophy. Cell. 1998 Apr 17;93(2):215-28. PMID:9568714
  14. ↑ 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
  15. ↑ Heineke J, Ruetten H, Willenbockel C, Gross SC, Naguib M, Schaefer A, Kempf T, Hilfiker-Kleiner D, Caroni P, Kraft T, Kaiser RA, Molkentin JD, Drexler H, Wollert KC. Attenuation of cardiac remodeling after myocardial infarction by muscle LIM protein-calcineurin signaling at the sarcomeric Z-disc. Proc Natl Acad Sci U S A. 2005 Feb 1;102(5):1655-60. Epub 2005 Jan 21. PMID:15665106 doi:10.1073/pnas.0405488102
  16. ↑ 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
  17. ↑ 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
  18. ↑ PMID: 10448862; 10448861
  19. ↑ Naya FJ, Mercer B, Shelton J, Richardson JA, Williams RS, Olson EN. Stimulation of slow skeletal muscle fiber gene expression by calcineurin in vivo. J Biol Chem. 2000 Feb 18;275(7):4545-8. PMID:10671477
  20. ↑ Molkentin JD, Lu JR, Antos CL, Markham B, Richardson J, Robbins J, Grant SR, Olson EN. A calcineurin-dependent transcriptional pathway for cardiac hypertrophy. Cell. 1998 Apr 17;93(2):215-28. PMID:9568714
  21. ↑ 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
  22. ↑ Turska-Kmiec A, Jankowska I, Pawlowska J, Kalicinski P, Kawalec W, Tomyn M, Markiewicz M, Teisseyre J, Czubkowski P, Rekawek J, Socha J. Reversal of tacrolimus-related hypertrophic cardiomyopathy after conversion to rapamycin in a pediatric liver transplant recipient. Pediatr Transplant. 2007 May;11(3):319-23. PMID:17430490 doi:10.1111/j.1399-3046.2006.00633.x
  23. ↑ Tsao L, Neville C, Musaro A, McCullagh KJ, Rosenthal N. Revisiting calcineurin and human heart failure. Nat Med. 2000 Jan;6(1):2-3. PMID:10613792 doi:10.1038/71478

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