Noureddine Maya, Mikolajek Halina, Morgan Neil V, Denning Chris, Loughna Siobhan, Gehmlich Katja, Mohammed Fiyaz
Department of Cardiovascular Sciences, School of Medical Sciences, College of Medicine and Health University of Birmingham, Birmingham, UK.
Diamond Light Source Ltd., Harwell Science and Innovation Campus , Didcot, UK.
J Gen Physiol. 2025 Mar 3;157(2). doi: 10.1085/jgp.202413684. Epub 2025 Feb 7.
α-actinin (ACTN) is a pivotal member of the actin-binding protein family, crucial for the anchoring and organization of actin filaments within the cytoskeleton. Four isoforms of α-actinin exist: two non-muscle isoforms (ACTN1 and ACTN4) primarily associated with actin stress fibers and focal adhesions, and two muscle-specific isoforms (ACTN2 and ACTN3) localized to the Z-disk of the striated muscle. Although these isoforms share structural similarities, they exhibit distinct functional characteristics that reflect their specialized roles in various tissues. Genetic variants in α-actinin isoforms have been implicated in a range of pathologies, including cardiomyopathies, thrombocytopenia, and non-cardiovascular diseases, such as nephropathy. However, the precise impact of these genetic variants on the α-actinin structure and their contribution to disease pathogenesis remains poorly understood. This review provides a comprehensive overview of the structural and functional attributes of the four α-actinin isoforms, emphasizing their roles in actin crosslinking and sarcomere stabilization. Furthermore, we present detailed structural modeling of select ACTN1 and ACTN2 variants to elucidate mechanisms underlying disease pathogenesis, with a particular focus on macrothrombocytopenia and hypertrophic cardiomyopathy. By advancing our understanding of α-actinin's role in both normal cellular function and disease states, this review lays the groundwork for future research and the development of targeted therapeutic interventions.
α-辅肌动蛋白（ACTN）是肌动蛋白结合蛋白家族的关键成员，对细胞骨架内肌动蛋白丝的锚定和组织至关重要。α-辅肌动蛋白存在四种异构体：两种非肌肉异构体（ACTN1和ACTN4）主要与肌动蛋白应力纤维和粘着斑相关，以及两种肌肉特异性异构体（ACTN2和ACTN3）定位于横纹肌的Z盘。尽管这些异构体具有结构相似性，但它们表现出不同的功能特征，反映了它们在各种组织中的特殊作用。α-辅肌动蛋白异构体的基因变异与一系列病理状况有关，包括心肌病、血小板减少症以及非心血管疾病，如肾病。然而，这些基因变异对α-辅肌动蛋白结构的精确影响及其对疾病发病机制的贡献仍知之甚少。本综述全面概述了四种α-辅肌动蛋白异构体的结构和功能特性，强调了它们在肌动蛋白交联和肌节稳定中的作用。此外，我们展示了选定的ACTN1和ACTN2变体的详细结构模型，以阐明疾病发病机制的潜在机制，特别关注巨大血小板减少症和肥厚型心肌病。通过增进我们对α-辅肌动蛋白在正常细胞功能和疾病状态中作用的理解，本综述为未来的研究和靶向治疗干预的开发奠定了基础。
