Biological properties of α-actinin-2 and its role and mechanisms in disease development

Figures

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  Figure 1. Schematic diagram of the molecular structure and conformational states of α-actinin-2. As reported by Euripedes de Almeida Ribeiro Jr et al. in 2014 (PMID: 25433700), α-actinin-2 exists in both closed and open conformations and functions as a counter-parallel homodimer with a molecular weight exceeding 200 kDa. Structurally, it consists of four distinct segments corresponding to functional domains: the green segment represents the four spectrin-like repeat (SR) sequences in the central region, the red segment denotes the N-terminal actin-binding domain (ABD), the yellow segment corresponds to the two pairs of EF-hand motifs (EF) within the C-terminal calmodulin-like domain (CAMD), and the blue segment is the neck region connecting these functional domains. This structural organization endows α-actinin-2 with the capabilities of binding actin filaments, forming antiparallel homodimers, and regulating calcium levels, which lays the foundation for its physiological functions.

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  Figure 2. Subcellular distribution of α-actinin-2 in cardiomyocytes and the structural basis of muscle contraction. (Top) Schematic of a cardiac sarcomere illustrating the precise localization of α-actinin-2 specifically at the Z-discs. In this panel, the blue thin lines represent the Z-discs and the anchored thin (actin) filaments, whereas the red thick lines indicate the thick (myosin) filaments within the A-band. α-actinin-2 acts as a crucial cross-linker at the Z-discs to maintain the structural integrity of the sarcomere. (Bottom) Molecular view of the contractile apparatus transitioning from a relaxed state to a contracted state, highlighting the sliding interaction between thick (myosin) and thin (actin) filaments driven by calcium binding and cross-bridge formation.

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  Figure 3. α-actinin-2 functions as a pleiotropic signaling scaffold integrating diverse physiological pathways. The schematic illustrates how α-actinin-2 coordinates distinct downstream effects across different tissues: (Top, Atrial Fibrosis) it exacerbates fibrosis by enhancing TGF-β1/Smad signaling; (Right, Nervous System) it regulates synaptic plasticity via interactions with NMDA receptors and CaMKII; (Bottom Right, Cardiac Structure) it anchors the Dystrophin-Glycoprotein Complex (DGC) via Ptpn23 to maintain T-tubule architecture; (Bottom Left, Maturation) it promotes cardiomyocyte maturation through the HSP90A/mTOR axis; and (Left, Metastasis) it drives cancer cell migration via an NF-κB positive feedback loop.

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  Figure 4. Multidimensional landscape of α-actinin-2 in disease mechanisms, research models, and clinical manifestations. (A) Pathogenic Divergence: Distinguishes between structural diseases (cardiomyopathies, myopathies) primarily caused by specific gene mutations (left), and systemic disorders (neurodegenerative, metabolic, cancer) driven by altered expression levels (right). (B) Research Model Gaps: Highlights the current reliance on rodent and cell models, pointing out the critical lack of non-human primate models (indicated by “?”) which limits translational precision. (C) Systemic Impact: Visualizes the broad clinical spectrum of α-actinin-2 dysfunction, emphasizing its potential as a diagnostic biomarker and therapeutic target across cardiac, neurological, muscular, and metabolic systems.

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  Figure 5. Structural mapping of pathogenic mutations across the functional domains of α-actinin-2. The schematic illustrates the distinct spatial distribution of disease-associated mutations. Structural perturbations within the actin-binding domain (ABD; p.Met228Thr, p.Thr247Met, p.Gly111Val, p.Ala119Thr) are predominantly linked to hypertrophic cardiomyopathy (HCM). Meanwhile, variants in the central rod domain (SR1–SR4; p.Glu583Ala, p.Glu628Gly, p.Tyr473Cys) correlate with dilated (DCM) and arrhythmogenic (ACM) cardiomyopathies. Mutations that alter the EF-hand motifs (p.Arg506Gly) or cause extreme C-terminal truncations (p.Q830Hfs*73, c.2558del) strongly drive arrhythmogenic right ventricular cardiomyopathy (ARVC), severe restrictive cardiomyopathy (RCM), and skeletal myopathies.