Group:MUZIC:CARP
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]
| |||||||||
| 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 [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 FunctionGene 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]
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], [5]. 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 [6]. 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 [5], desmin [7], and muscle-specific RING finger proteins MuRF1/MuRF2 [8] indicating its structural role. CARP/Ankrd1 also binds several transcription factors such as YB1 and p53.
RefrencesRefrences
- ↑ 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
- ↑ 2.0 2.1 2.2 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
- ↑ 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
- ↑ 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
- ↑ 5.0 5.1 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
- ↑ 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
- ↑ 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
- ↑ 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