Structural and functional insights into α-actinin isoforms and their implications in cardiovascular disease.

IF 3.3 2区 医学 Q1 PHYSIOLOGY
Journal of General Physiology Pub Date : 2025-03-03 Epub Date: 2025-02-07 DOI:10.1085/jgp.202413684
Maya Noureddine, Halina Mikolajek, Neil V Morgan, Chris Denning, Siobhan Loughna, Katja Gehmlich, Fiyaz Mohammed
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引用次数: 0

Abstract

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-肌动蛋白异构体的结构和功能及其在心血管疾病中的意义。
α-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-肌动蛋白有四种异构体:两种非肌肉异构体(ACTN1和ACTN4)主要与肌动蛋白应激纤维和局灶粘连相关,两种肌肉特异性异构体(ACTN2和ACTN3)定位于横纹肌z盘。虽然这些同工异构体具有结构上的相似性,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-肌动蛋白异构体的遗传变异与一系列疾病有关,包括心肌病、血小板减少症和非心血管疾病,如肾病。然而,这些基因变异对α-肌动蛋白结构的确切影响及其对疾病发病机制的贡献仍然知之甚少。本文综述了四种α-肌动蛋白亚型的结构和功能特性,重点介绍了它们在肌动蛋白交联和肌节稳定中的作用。此外,我们提出了选择ACTN1和ACTN2变异的详细结构模型,以阐明潜在的疾病发病机制,特别关注巨血小板减少症和肥厚性心肌病。通过进一步了解α-肌动蛋白在正常细胞功能和疾病状态中的作用,本综述为未来的研究和靶向治疗干预的发展奠定了基础。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
6.00
自引率
10.50%
发文量
88
审稿时长
6-12 weeks
期刊介绍: General physiology is the study of biological mechanisms through analytical investigations, which decipher the molecular and cellular mechanisms underlying biological function at all levels of organization. The mission of Journal of General Physiology (JGP) is to publish mechanistic and quantitative molecular and cellular physiology of the highest quality, to provide a best-in-class author experience, and to nurture future generations of independent researchers. The major emphasis is on physiological problems at the cellular and molecular level.
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