Group:MUZIC:Calcineurin

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==Sequence Annotation==
==Sequence Annotation==
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The calcium/calmodulin-dependent phosphatase calcineurin is composed by two chains: chain A [http://www.uniprot.org/uniprot/Q08209 Q08209], (CnA) which is the catalytic subunit and chain B [http://www.uniprot.org/uniprot/P63098 P63098](CnB), which confers calcium sensitivity. <ref>PMID: 8524402</ref>Those two subunits are tighlty bound and they only disociate under denaturant conditions.<ref>PMID: 8524402</ref><ref>PMID: 9199180</ref> 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. <ref>PMID: 8204620</ref>
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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) <ref>PMID: 8524402</ref>. Each of the subunits has alternative names in the literature, as it is shown in their uniprotKB entries [http://www.uniprot.org/uniprot/Q08209 Q08209] and [http://www.uniprot.org/uniprot/P63098 P63098]. The CnA comprises a globular catalytic domain (residues 1 to 301), the 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). The CnB is composed of four EF hands spanning from residue 18 to 163.
== Structure ==
== Structure ==

Revision as of 17:36, 17 January 2013

Contents

Introduction

Calcineurin, a serine-threonine phosphatase, is a heterodimeric protein composed of a catalytic subunit with phosphatase activity and a regulatory subunit, Ca2+ regulated. It 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) family, which dephosphorylation promote their translocation to the nucleus, following transcriptional activation of their target genes ([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. The CnA comprises a globular catalytic domain (residues 1 to 301), the 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). The CnB is composed of four EF hands spanning from residue 18 to 163.

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 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. [4]

Function and Interactions

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. [5]

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.[6] 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. [7] As positive modulator it has been described Lmcd1/Dyxin, which up-regulation caused hypertrophy accompanied by strong activation of calcineurin signalling. [8]

Pathology

The up regulation of the calcineurin phosphatase activity is one of the factors that lead to development of hypertrophic cardiomyopathy (HCM). It is known that dephosphorylation of NFAT by calcineurin is a key signal for activating cell proliferation and as a consequence of up regulation of this signal cells entry into a pathological state of proliferation that causes HCM. [9]

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. ↑ 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
  5. ↑ 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
  6. ↑ 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
  7. ↑ 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
  8. ↑ 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
  9. ↑ Dickhout JG, Carlisle RE, Austin RC. Interrelationship between cardiac hypertrophy, heart failure, and chronic kidney disease: endoplasmic reticulum stress as a mediator of pathogenesis. Circ Res. 2011 Mar 4;108(5):629-42. PMID:21372294 doi:10.1161/CIRCRESAHA.110.226803

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