Ankyrin Repeat Domain 1 Protein: A Functionally Pleiotropic Protein with Cardiac Biomarker Potential

Figures

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  Figure 1. Schematic representation of human ankyrin repeat domain 1 (ANKRD1) structure, binding partners and phosphorylation and cleavage sites. The ANKRD1 protein has 319 amino acids consisting of a coiled-coil domain, two PEST-like regions, an ankyrin repeat domain consisting of five ankyrin repeats (ANK), two putative nuclear localization signals (NLSs) and one potential nuclear export signal (NES). ANKRD1 has two binding sites for titin and five binding sites for calsequestrin (CASQ2) which are indicated by blue solid lines. Regions or residues involved in interaction with myopalladin, desmin, talin-1, four-and-a-half LIM domains 2 (FHL2) and 14-3-3 proteins are also indicated accordingly. Experimentally verified phosphorylation sites (yellow-circled P) and the protein kinases (PKCα, protein kinase C; ROCK, Rho kinase) responsible are indicated. Regions harboring cleavage sites by caspase-3 (CASP3) and calpain 3 are indicated by solid red lines. Predicted caspase-1 (CASP1) cleavage site is marked by a dashed line. Diagram is not drawn to scale.

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  Figure 2. Predicted Swiss Model of ANKRD1. The 3D structure of ANKRD1 from Pro122 to Thr313 is shown (blue) with hydrophobic residues indicated in red. Ankyrin repeat units 1 (Tyr152–Phe181), 2 (Leu185–Ala214), 3 (Leu218–Ala247), 4 (Glu251–Ile280) and 5 (Ala284–Arg315) are indicated by green and black arrows showing the start and end of each unit, respectively. The end of ankyrin repeat unit 5 terminating at Arg315 is not shown.

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  Figure 3. Schematic diagram showing the pathological cardiac functions of ANKRD1 in relation to hypertrophy, fibrosis and apoptosis. Hypertrophic stress response: Pressure overload rapidly increases the expression of cardiac ANKRD1 and inhibits the ERK and TGF-β/Smad pathways, leading to the attenuation of hypertrophy. This is thought to be an adaptive and protective response. Conversely, increase in ANKRD1 also exacerbates pathological cardiac remodeling through activation of the calcineurin/NFAT pathway, a signaling pathway known to have an important role in cardiac hypertrophy. Hence, the role of ANKRD1 in cardiac hypertrophy is still controversial; Fibrosis: Nuclear ANKRD1 interacts with nucleolin and hinders the binding of positive transcriptional activators to the AP-1 promoter site, thus inhibiting transcription of the Mmp13 gene. This limits the expression of MMP13 to within appropriate physiological levels to enable successful tissue repair. On the other hand, expression of Ankrd1 is increased in plasminogen activator inhibitor-1 knockout mouse. This in turn induces the elevation of Egr1 which is associated with cardiac fibrosis. In addition, the concomitant upregulation of…