Group:MUZIC:CARP

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Ankrd1/CARP

Introduction

The cardiac ankyrin repeat protein (CARP/Ankrd1) belongs together with the ankyrin repeat domain 2 (Ankrd2/Arpp) and the diabetes associated ankyrin repeat protein (DARP) 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 that interacts with the transcriptional factor YB-1 and a cardiac doxorubicin-responsive protein[2],[3]. In physiological tissues, Ankrd1 is highly expressed in cardiac muscle and is 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].

Sequence Annotation

The 319 aminoacid sequence of CARP/Ankrd1 is comprising an N-terminal coiled-coil followed by 5 ankyrin repoeats. The sequences of the human, mouse and rabbit proteins are available from Uniprot. 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 [9].


Structure

Currently there is no structure available for the Ankrd1 even though ankyrin repeats are very common, modular, protein–protein interaction motifs in nature. Idealized ankyrin repeat motifs that show similarity to Ankrd1 have been determined by X-ray crystallography (PDB Entries: 1n0r and 1n11)

To understand the structural determinants of this family of proteins and extract the consensus information that defines the architecture of this motif, we have designed a series of idealized ankyrin repeat proteins containing one, two, three, or four repeats by using statistical analysis of ≈4,000 ankyrin repeat sequences from the PFAM database. Biophysical and x-ray crystallographic studies of the three and four repeat constructs (3ANK and 4ANK) to 1.26 and 1.5 Å resolution, respectively, demonstrate that these proteins are well-folded, monomeric, display high thermostability, and adopt a very regular, tightly packed ankyrin repeat fold.

Gene Function and Interactions

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 also co-localizes in the central I-band N2A region of titin. Specifically the binding site of Ankrd1 is located within its ankyrin repeat region and it interacts with a tyrosine-rich motif lying between two Ig-like motifs (I80 and I81)[1]. The cleavage of Ankrd1 by calpain 3 disrupts the bipartite NLS potentially affecting its nuclear transport[10] and the cleavage site is located at the N terminus of Ankrd1 between amino acids 30 and 71[11]. CARP/Ankrd1 binds the sarcomeric protein cardiac calsequestrin-2 (CASQ2)[8]. This interaction is mediated at least partially by the binding sites localized within the ankyrin repeats and the coiled-coil domain of Ankrd1. It has also been reported that the Ankrd1 is interacting with the sarcomeric proteins myopalladin[12], desmin[13] and the muscle-specific RING finger proteins MuRF1/MuRF2[14] indicating its important structural role. CARP/Ankrd1 also binds calpain 3 and several transcription factors such as YB1 and p53[10].

Pathology

Ankrd1 has been found to be induced in the hypertrophy, during cardiac ventricle overload[15] in the skeletal muscle under certain conditions such as exercise[16], denervation [17], work overload hypertrophy[18] and muscle pathologies[19],[20],[21]. It could also 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[22]. The Ankrd1 expression is increased in patients with left ventricular dilated and ischemic cardiomyopathies[23] and it has been identified as a candidate gene with a role in congenital heart disease [24].


Refrences

  1. ↑ 1.0 1.1 1.2 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 3.2 3.3 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
  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. ↑ 8.0 8.1 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. ↑ 9.0 9.1 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. ↑ 10.0 10.1 Laure L, Daniele N, Suel L, Marchand S, Aubert S, Bourg N, Roudaut C, Duguez S, Bartoli M, Richard I. A new pathway encompassing calpain 3 and its newly identified substrate cardiac ankyrin repeat protein is involved in the regulation of the nuclear factor-kappaB pathway in skeletal muscle. FEBS J. 2010 Oct;277(20):4322-37. doi: 10.1111/j.1742-4658.2010.07820.x., Epub 2010 Sep 22. PMID:20860623 doi:10.1111/j.1742-4658.2010.07820.x
  11. ↑ Hayashi C, Ono Y, Doi N, Kitamura F, Tagami M, Mineki R, Arai T, Taguchi H, Yanagida M, Hirner S, Labeit D, Labeit S, Sorimachi H. Multiple molecular interactions implicate the connectin/titin N2A region as a modulating scaffold for p94/calpain 3 activity in skeletal muscle. J Biol Chem. 2008 May 23;283(21):14801-14. Epub 2008 Feb 29. PMID:18310072 doi:10.1074/jbc.M708262200
  12. ↑ 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
  13. ↑ 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
  14. ↑ 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
  15. ↑ 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
  16. ↑ Lehti M, Kivela R, Komi P, Komulainen J, Kainulainen H, Kyrolainen H. Effects of fatiguing jumping exercise on mRNA expression of titin-complex proteins and calpains. J Appl Physiol. 2009 Apr;106(4):1419-24. Epub 2009 Jan 15. PMID:19150862 doi:10.1152/japplphysiol.90660.2008
  17. ↑ 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
  18. ↑ 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
  19. ↑ Nakamura K, Nakada C, Takeuchi K, Osaki M, Shomori K, Kato S, Ohama E, Sato K, Fukayama M, Mori S, Ito H, Moriyama M. Altered expression of cardiac ankyrin repeat protein and its homologue, ankyrin repeat protein with PEST and proline-rich region, in atrophic muscles in amyotrophic lateral sclerosis. Pathobiology. 2002-2003;70(4):197-203. PMID:12679596 doi:10.1159/000069329
  20. ↑ Nakada C, Tsukamoto Y, Oka A, Nonaka I, Takeda S, Sato K, Mori S, Ito H, Moriyama M. Cardiac-restricted ankyrin-repeated protein is differentially induced in duchenne and congenital muscular dystrophy. Lab Invest. 2003 May;83(5):711-9. PMID:12746480
  21. ↑ Nakada C, Oka A, Nonaka I, Sato K, Mori S, Ito H, Moriyama M. Cardiac ankyrin repeat protein is preferentially induced in atrophic myofibers of congenital myopathy and spinal muscular atrophy. Pathol Int. 2003 Oct;53(10):653-8. PMID:14516314
  22. ↑ Wu CL, Kandarian SC, Jackman RW. Identification of genes that elicit disuse muscle atrophy via the transcription factors p50 and Bcl-3. PLoS One. 2011 Jan 13;6(1):e16171. PMID:21249144 doi:10.1371/journal.pone.0016171
  23. ↑ 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
  24. ↑ 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

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