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

Journal article : Review

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.

Authors: Noureddine, M; Mikolajek, H; Morgan, NV; Denning, C; Loughna, S

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Rockefeller University Press
• Journal: Journal of General Physiology
• Volume: 157
• Issue: 2
• Article number: e202413684
• Place of publication: United States
• Publication date: 2025-02-07
• Acceptance date: 2025-01-13
• DOI: 10.1085/jgp.202413684
• EISSN: 1540-7748
• ISSN: 0022-1295
• Pmid: 39918740
• Language: English
• Keywords: heart disease; cardiovascular diseases; protein isoforms; cardiovascular; actinin
• Subtype: Review