Ankyrin Repeat Domain 1: A Key Regulatory Factor and Emerging Therapeutic Target in Heart Disease

Figures

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  Fig. 1.. Gene and protein structural features of ANKRD1 (Created with BioGDP.com) [26]. (A) The ANKRD1 gene consists of a short 5’ UTR, a coding region that encodes 319 amino acids, and a long 3’ UTR containing a degradation motif. Its promoter, located upstream of the 5’ UTR, contains multiple cis-acting elements. The coding region encompasses proline, glutamic acid, serine, and threonine (PEST) sequences, a nuclear localization signal (NLS), a nuclear export signal (NES) and ankyrin repeats. Several phosphorylation sites have been predicted and partially validated (Thr11-PKCα, Thr116-ROCK1, Ser314-ROCK1). These sites are primarily distributed flanking the ankyrin repeat domains and near clusters of basic amino acids, regulating the subcellular localization and signaling complex assembly of ANKRD1. (B) Potential acetylation sites (indicated in red) and ubiquitination sites (indicated in yellow) have been predicted using the PhosphoSitePlus database, suggesting complex post-translational regulation of ANKRD1 function. PKCα, protein kinase C; ROCK, Rho kinase.

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  Fig. 2.. Intracellular localization and functional regulation of ANKRD1 (created with BioGDP.com) [26]. (A) As a regulatory factor, ANKRD1 interacts with various proteins such as YB-1 and GATA4 in the nucleus to modulate the expression of Atrial Natriuretic Factor (ANF) and Myosin Light Chain 2, Ventricular (MLC-2v) genes; In the cytoplasm, ANKRD1 binds to the N2A domain of titin and interacts with calsequestrin-2 (CASQ2) and myopalladin, contributing to the regulation of stretch sensing and sarcomere integrity; The C-terminal region of ANKRD1 mRNA can be tagged with sequences such as HA or Myc, with its biological functions indicated. (B) ANKRD1 is specifically localized to the I-band of the sarcomere in cardiomyocytes, where it binds to the N2A domain of the giant sarcomeric protein titin to form a mechanosensory and transduction complex. This complex interacts with sarcomere-associated proteins such as CASQ2 and myopalladin to maintain sarcomeric structural integrity. Upon phenylephrine (PE) stimulation, the ANKRD1-titin complex recruits and phosphorylates extracellular signal-regulated kinases 1 and 2 (ERK1/2), which in turn phosphorylate GATA4, leading to the assembly of a signaling…