Group:MUZIC:CARP: Difference between revisions

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== Gene Function ==
== Gene Function ==


CARP/Ankrd1 plays a structural role by interacting with the Z disc protein titin. It is a part of the titin-mechanosensory signaling complex in the sarcomere and in response to stretch it translocates to the nucleus where it participates in the regulation of cardiac genes as a transcriptional co-repressor. <ref name='two' /> <ref>pmid 9278441 </ref>. CARP/Ankrd1 has been found to be induced in the hypertrophy, during cardiac ventricle overload.<ref>pmid 10904011 </ref> and in denervated skeletal muscle <ref> pmid 9382869 </ref>, <ref> pmid 12004005 </ref>. In skeletal muscle, CARP/Ankrd1 is up-regulated in response to a variety of mechanical stresses, including acute resistance exercise.<ref> pmid 11758972 </ref> and work overload hypertrophy. <ref> pmid 11744623 </ref> CARP/Ankrd1 expression is increased in patients with left ventricular dilated and ischemic cardiomyopathies  <ref> pmid 12054667 </ref>, and it has been identified as a candidate gene with a role in congenital heart disease.<ref> pmid 18273862 </ref>
CARP/Ankrd1 plays a structural role by interacting with the Z disc protein titin. It is a part of the titin-mechanosensory signaling complex in the sarcomere and in response to stretch it translocates to the nucleus where it participates in the regulation of cardiac genes as a transcriptional co-repressor. <ref name='two' /> CARP/Ankrd1 has been found to be induced in the hypertrophy, during cardiac ventricle overload.<ref>pmid 10904011 </ref> and in denervated skeletal muscle <ref> pmid 9382869 </ref>, <ref> pmid 12004005 </ref>. In skeletal muscle, CARP/Ankrd1 is up-regulated in response to a variety of mechanical stresses, including acute resistance exercise.<ref> pmid 11758972 </ref> and work overload hypertrophy. <ref> pmid 11744623 </ref> CARP/Ankrd1 expression is increased in patients with left ventricular dilated and ischemic cardiomyopathies  <ref> pmid 12054667 </ref>, and it has been identified as a candidate gene with a role in congenital heart disease.<ref> pmid 18273862 </ref>


==Localization==  
==Localization==  

Revision as of 13:35, 16 August 2011


Introduction

Cardiac ankyrin repeat protein (CARP/Ankrd1) together with ankyrin repeat domain 2 (Ankrd2/Arpp) and with diabetes associated ankyrin repeat protein (DARP), belongs to a conserved muscle ankyrin repeat protein (MARP) family CARDIAC ANKYRIN REPEAT PROTEIN; CARP belongs to the conserved muscle ankyrin repeat protein (MARP) family.[1] CARP/Ankrd1 has been independently identified by several groups as a cytokine-inducible transcriptional regulator, a protein interacting with transcriptional factor YB-1, and a cardiac doxorubicin-responsive protein [1],[2]. In normal tissues, Ankrd1 is highly expressed in cardiac muscle and detectable in skeletal muscles. [2] It is an early differentiation marker during cardiogenesis with a high expression level in developing heart [2],[3]. Mutations in the ANKRD1 gene are responsible for human dilated cardiomyopathy.[4]

PDB ID 1n11

Drag the structure with the mouse to rotate
1n0r, resolution 1.50Å ()
Ligands:
Related: 1n0q
Resources: FirstGlance, OCA, PDBsum, RCSB
Coordinates: save as pdb, mmCIF, xml



StructureStructure

Found on chromosome 10 in humans and 19 in mouse, the ankrd1 gene structure is highly conserved, with nine exons and a canonical TATA box in the proximal promoter. Other canonical response elements identified in the 5' flanking sequence of CARP include GATA sites, E-box elements, a CCAC box, a CAGA box, and M-CAT, activator protein-1, SP-1, p53 binding sites.[5], [6] CARP protein sequence and domain organization is highly conserved among mammalian species: a bipartite nuclear localization signal, a PEST-like sequence, four highly conserved ankyrin-like repeats and another less conserved half repeat, and numerous potential modification sites for phosphorylation, glycosylation, and myristilation. [3]

Gene FunctionGene Function

CARP/Ankrd1 plays a structural role by interacting with the Z disc protein titin. It is a part of the titin-mechanosensory signaling complex in the sarcomere and in response to stretch it translocates to the nucleus where it participates in the regulation of cardiac genes as a transcriptional co-repressor. [2] CARP/Ankrd1 has been found to be induced in the hypertrophy, during cardiac ventricle overload.[7] and in denervated skeletal muscle [8], [9]. In skeletal muscle, CARP/Ankrd1 is up-regulated in response to a variety of mechanical stresses, including acute resistance exercise.[10] and work overload hypertrophy. [11] CARP/Ankrd1 expression is increased in patients with left ventricular dilated and ischemic cardiomyopathies [12], and it has been identified as a candidate gene with a role in congenital heart disease.[13]

LocalizationLocalization

CARP/Ankrd1 is found in the central I-band of the sarcomere, where it binds the N2A region of titin and the amino-terminus of the nebulin anchoring protein myopalladin. [1], [14]. CARP/Ankrd1 shuttles to the nucleus where it participates in the regulation of gene expression, serving as mediator between the stress and transcriptional response.

CARP InteractionsCARP Interactions

CARP/Ankrd1 binds the sarcomeric protein titin [1] and cardiac calsequestrin-2, CASQ2 [15]. These interaction are mediated, at least partially, by the binding sites localized within the ankyrin repeats and coiled-coil domain. CARP/Ankrd1 can also interact with the sarcomeric proteins myopalladin [16], desmin [17], and muscle-specific RING finger proteins MuRF1/MuRF2 [18] indicating its structural role. CARP/Ankrd1 also binds several transcription factors such as YB1 and p53.

RefrencesRefrences

  1. ↑ 1.0 1.1 1.2 1.3 Miller MK, Bang ML, Witt CC, Labeit D, Trombitas C, Watanabe K, Granzier H, McElhinny AS, Gregorio CC, Labeit S. The muscle ankyrin repeat proteins: CARP, ankrd2/Arpp and DARP as a family of titin filament-based stress response molecules. J Mol Biol. 2003 Nov 7;333(5):951-64. PMID:14583192
  2. ↑ 2.0 2.1 2.2 2.3 Zou Y, Evans S, Chen J, Kuo HC, Harvey RP, Chien KR. CARP, a cardiac ankyrin repeat protein, is downstream in the Nkx2-5 homeobox gene pathway. Development. 1997 Feb;124(4):793-804. PMID:9043061
  3. ↑ 3.0 3.1 Jeyaseelan R, Poizat C, Baker RK, Abdishoo S, Isterabadi LB, Lyons GE, Kedes L. A novel cardiac-restricted target for doxorubicin. CARP, a nuclear modulator of gene expression in cardiac progenitor cells and cardiomyocytes. J Biol Chem. 1997 Sep 5;272(36):22800-8. PMID:9278441
  4. ↑ Duboscq-Bidot L, Charron P, Ruppert V, Fauchier L, Richter A, Tavazzi L, Arbustini E, Wichter T, Maisch B, Komajda M, Isnard R, Villard E. Mutations in the ANKRD1 gene encoding CARP are responsible for human dilated cardiomyopathy. Eur Heart J. 2009 Sep;30(17):2128-36. Epub 2009 Jun 12. PMID:19525294 doi:10.1093/eurheartj/ehp225
  5. ↑ Kuo H, Chen J, Ruiz-Lozano P, Zou Y, Nemer M, Chien KR. Control of segmental expression of the cardiac-restricted ankyrin repeat protein gene by distinct regulatory pathways in murine cardiogenesis. Development. 1999 Oct;126(19):4223-34. PMID:10477291
  6. ↑ Kojic S, Nestorovic A, Rakicevic L, Belgrano A, Stankovic M, Divac A, Faulkner G. A novel role for cardiac ankyrin repeat protein Ankrd1/CARP as a co-activator of the p53 tumor suppressor protein. Arch Biochem Biophys. 2010 Oct 1;502(1):60-7. Epub 2010 Jul 3. PMID:20599664 doi:10.1016/j.abb.2010.06.029
  7. ↑ Aihara Y, Kurabayashi M, Saito Y, Ohyama Y, Tanaka T, Takeda S, Tomaru K, Sekiguchi K, Arai M, Nakamura T, Nagai R. Cardiac ankyrin repeat protein is a novel marker of cardiac hypertrophy: role of M-CAT element within the promoter. Hypertension. 2000 Jul;36(1):48-53. PMID:10904011
  8. ↑ Baumeister A, Arber S, Caroni P. Accumulation of muscle ankyrin repeat protein transcript reveals local activation of primary myotube endcompartments during muscle morphogenesis. J Cell Biol. 1997 Dec 1;139(5):1231-42. PMID:9382869
  9. ↑ Tsukamoto Y, Senda T, Nakano T, Nakada C, Hida T, Ishiguro N, Kondo G, Baba T, Sato K, Osaki M, Mori S, Ito H, Moriyama M. Arpp, a new homolog of carp, is preferentially expressed in type 1 skeletal muscle fibers and is markedly induced by denervation. Lab Invest. 2002 May;82(5):645-55. PMID:12004005
  10. ↑ Chen R, Harrod KS, Olson JW, Gillespie MN. Regulation of gadd153 mRNA expression by hypoxia in pulmonary artery smooth muscle cells. Res Commun Mol Pathol Pharmacol. 2000 Jul-Aug;108(1-2):3-14. PMID:11758972
  11. ↑ Carson JA, Nettleton D, Reecy JM. Differential gene expression in the rat soleus muscle during early work overload-induced hypertrophy. FASEB J. 2002 Feb;16(2):207-9. Epub 2001 Dec 14. PMID:11744623 doi:10.1096/fj.01-0544fje
  12. ↑ Zolk O, Frohme M, Maurer A, Kluxen FW, Hentsch B, Zubakov D, Hoheisel JD, Zucker IH, Pepe S, Eschenhagen T. Cardiac ankyrin repeat protein, a negative regulator of cardiac gene expression, is augmented in human heart failure. Biochem Biophys Res Commun. 2002 May 24;293(5):1377-82. PMID:12054667 doi:10.1016/S0006-291X(02)00387-X
  13. ↑ Cinquetti R, Badi I, Campione M, Bortoletto E, Chiesa G, Parolini C, Camesasca C, Russo A, Taramelli R, Acquati F. Transcriptional deregulation and a missense mutation define ANKRD1 as a candidate gene for total anomalous pulmonary venous return. Hum Mutat. 2008 Apr;29(4):468-74. PMID:18273862 doi:10.1002/humu.20711
  14. ↑ Bang ML, Mudry RE, McElhinny AS, Trombitas K, Geach AJ, Yamasaki R, Sorimachi H, Granzier H, Gregorio CC, Labeit S. Myopalladin, a novel 145-kilodalton sarcomeric protein with multiple roles in Z-disc and I-band protein assemblies. J Cell Biol. 2001 Apr 16;153(2):413-27. PMID:11309420
  15. ↑ Torrado M, Nespereira B, Lopez E, Centeno A, Castro-Beiras A, Mikhailov AT. ANKRD1 specifically binds CASQ2 in heart extracts and both proteins are co-enriched in piglet cardiac Purkinje cells. J Mol Cell Cardiol. 2005 Feb;38(2):353-65. Epub 2005 Jan 26. PMID:15698842 doi:10.1016/j.yjmcc.2004.11.034
  16. ↑ Bang ML, Mudry RE, McElhinny AS, Trombitas K, Geach AJ, Yamasaki R, Sorimachi H, Granzier H, Gregorio CC, Labeit S. Myopalladin, a novel 145-kilodalton sarcomeric protein with multiple roles in Z-disc and I-band protein assemblies. J Cell Biol. 2001 Apr 16;153(2):413-27. PMID:11309420
  17. ↑ Witt SH, Labeit D, Granzier H, Labeit S, Witt CC. Dimerization of the cardiac ankyrin protein CARP: implications for MARP titin-based signaling. J Muscle Res Cell Motil. 2005;26(6-8):401-8. PMID:16450059 doi:10.1007/s10974-005-9022-9
  18. ↑ Witt CC, Witt SH, Lerche S, Labeit D, Back W, Labeit S. Cooperative control of striated muscle mass and metabolism by MuRF1 and MuRF2. EMBO J. 2008 Jan 23;27(2):350-60. Epub 2007 Dec 20. PMID:18157088 doi:10.1038/sj.emboj.7601952
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