Group:MUZIC:CARP

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'''Introduction'''
'''Introduction'''
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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.<ref name='one'>PMID 14583192 </ref> 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 <ref name='one' />,<ref name='two'>pmid 9043061 </ref>. In normal tissues, Ankrd1 is highly expressed in cardiac muscle and detectable in skeletal muscles. <ref name='two' /> It is an early differentiation marker during cardiogenesis with a high expression level in developing heart <ref name='two' />,<ref name='three'>pmid 9278441 </ref>. Mutations in the ANKRD1 gene are responsible for human dilated cardiomyopathy.<ref>pmid 19525294 </ref>
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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 <ref name='one'>PMID 14583192</ref>. 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 <ref name='two'>PMID 7730328</ref>,<ref name='three'>PMID 9043061</ref>. In normal tissues, Ankrd1 is highly expressed in cardiac muscle and detectable in skeletal muscles [3]. It is an early differentiation marker during cardiogenesis with a high expression level in developing heart. <ref
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name='three'>PMID 9043061</ref>, <ref name='four'>PMID 9278441</ref>. Mutations in the ANKRD1 gene are responsible for human dilated cardiomyopathy. <ref name='five'>PMID 14561590</ref>
{{STRUCTURE_1n0r| PDB=1n11}}
{{STRUCTURE_1n0r| PDB=1n11}}
== Structure ==
== Structure ==
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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 [6], [7]. 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. Binding sites for sarcomeric proteins titin [1], calsequestrin-2 (CASQ2) [8] and telethonin/T-cap [9] are located in ankyrin repeat region of Ankrd1. It possesses two PEST motifs. Mutations or deletion of the PEST region increase Ankrd1 protein stability in vivo [10].
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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 <ref name='six'>PMID 10477291</ref>,<ref name='seven'>PMID 20599664</ref>. 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. Binding sites for sarcomeric proteins titin <ref name='one'>PMID 14583192</ref>, calsequestrin-2 (CASQ2)<ref name='eight'>PMID 15698842</ref> and telethonin/T-cap <ref name='nine'>PMID 22016770</ref> are located in ankyrin repeat region of Ankrd1. It possesses two PEST motifs. Mutations or deletion of the PEST region increase Ankrd1 protein stability in vivo <ref name='ten'>PMID 22016770</ref>.
== Gene Function ==
== Gene Function ==

Revision as of 13:05, 30 November 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 [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 [2],[3]. In normal tissues, Ankrd1 is highly expressed in cardiac muscle and detectable in skeletal muscles [3]. It is an early differentiation marker during cardiogenesis with a high expression level in developing heart. [3], [4]. Mutations in the ANKRD1 gene are responsible for human dilated cardiomyopathy. [5]

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



Contents

Structure

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 [6],[7]. 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. Binding sites for sarcomeric proteins titin [1], calsequestrin-2 (CASQ2)[8] and telethonin/T-cap [9] are located in ankyrin repeat region of Ankrd1. It possesses two PEST motifs. Mutations or deletion of the PEST region increase Ankrd1 protein stability in vivo [10].

Gene Function

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 [3]. Ankrd1 has been found to be induced in the hypertrophy, during cardiac ventricle overload [11], in the skeletal muscle under certain conditions such as exercise [12], denervation [13], work overload hypertrophy [14] and muscle pathologies [15 16 17]. Ankrd1 could be involved in muscle disuse atrophy, since it was identified as an indirect target gene of two transcription factors (p50 and Bcl-3) associated with muscle wasting [18]. Ankrd1 expression is increased in patients with left ventricular dilated and ischemic cardiomyopathies [19], and it has been identified as a candidate gene with a role in congenital heart disease [20]

Localization

Ankrd1 localizes in the central I-band region, co-localizes with the titin-N2A region, more specifically with a tyrosine-rich motif lying between two Ig-like motifs (I80 and I81). Ankrd1 protein contains a binding site for titin within its ankyrin repeat region [1]. The cleavage of Ankrd1 by calpain 3 disrupts the bipartite NLS potentially affecting its nuclear transport [21]. The cleavage site for calpain 3 is at the N terminus of Ankrd1 between amino acids 30 and 71 [22].

CARP Interactions

CARP/Ankrd1 binds the sarcomeric protein titin [1] and cardiac calsequestrin-2, CASQ2 [8]. These interactions are mediated, at least partially, by the binding sites localized within the ankyrin repeats and coiled-coil domain. Ankrd1 can also interact with the sarcomeric proteins myopalladin [23], desmin [24], and muscle-specific RING finger proteins MuRF1/MuRF2 [25] indicating its structural role. CARP/Ankrd1 also binds calpain 3 (21) and several transcription factors such as YB1 and p53.

Refrences

  1. ↑ 1.0 1.1 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. ↑ Chu W, Burns DK, Swerlick RA, Presky DH. Identification and characterization of a novel cytokine-inducible nuclear protein from human endothelial cells. J Biol Chem. 1995 Apr 28;270(17):10236-45. PMID:7730328
  3. ↑ 3.0 3.1 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
  4. ↑ 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
  5. ↑ Barash IA, Mathew L, Ryan AF, Chen J, Lieber RL. Rapid muscle-specific gene expression changes after a single bout of eccentric contractions in the mouse. Am J Physiol Cell Physiol. 2004 Feb;286(2):C355-64. Epub 2003 Oct 15. PMID:14561590 doi:10.1152/ajpcell.00211.2003
  6. ↑ 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
  7. ↑ 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
  8. ↑ 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
  9. ↑ Belgrano A, Rakicevic L, Mittempergher L, Campanaro S, Martinelli VC, Mouly V, Valle G, Kojic S, Faulkner G. Multi-tasking role of the mechanosensing protein Ankrd2 in the signaling network of striated muscle. PLoS One. 2011;6(10):e25519. Epub 2011 Oct 10. PMID:22016770 doi:10.1371/journal.pone.0025519
  10. ↑ Belgrano A, Rakicevic L, Mittempergher L, Campanaro S, Martinelli VC, Mouly V, Valle G, Kojic S, Faulkner G. Multi-tasking role of the mechanosensing protein Ankrd2 in the signaling network of striated muscle. PLoS One. 2011;6(10):e25519. Epub 2011 Oct 10. PMID:22016770 doi:10.1371/journal.pone.0025519

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