Alpha-actinin-2 is a protein which in humans is encoded by the ACTN2 gene. [5] This gene encodes an alpha-actinin isoform that is expressed in both skeletal and cardiac muscles and functions to anchor myofibrillar actin thin filaments and titin to Z-discs.
Alpha-actinin-2 is a 103.8 kDa protein composed of 894 amino acids. [6] [7] Each molecule is rod-shaped (35 nm in length) and it homodimerizes in an anti-parallel fashion. Each monomer has an N-terminal actin-binding region composed of two calponin homology domains, two C-terminal EF hand domains, and four tandem spectrin-like repeats form the rod domain in the central region of the molecule. [8] The high-resolution crystal structure of human alpha-actinin 2 at 3.5 Å was recently resolved. [9] Alpha actinins belong to the spectrin gene superfamily which represents a diverse group of actin-binding cytoskeletal proteins, including spectrin, dystrophin, utrophin and fimbrin. [8] Skeletal, cardiac, and smooth muscle isoforms are localized to the Z-disc and analogous dense bodies, where they help anchor the myofibrillar actin filaments. Alpha-actinin 2 has been shown to interact with KCNA5, [10] [11] DLG1, [10] DISC1, [12] MYOZ1, [13] GRIN2B, [14] ADAM12, [15] ACTN3, [16] MYPN, [17] PDLIM3, [18] PKN, [19] MYOT, [20] TTN, [21] NMDAR, [22] SYNPO2, [23] LDB3, [24] and FATZ. [13]
The primary function of alpha-actinin-2 is to crosslink filamentous actin molecules and titin molecules from adjoining sarcomeres at Z-discs, a function that is modulated by phospholipids. [25] [26] It is clear from studies by Hampton et al. that this crosslinking can assume a variety of conformations, with preferences for 60° and 120° angles. [27] Alpha-actinin-2 also functions in docking signalling molecules at Z-discs, and additional studies have also implicated alpha-actinin-2 in the binding of cardiac ion channels, Kv1.5 in particular. [10]
Mutations in ACTN2 are associated with hypertrophic cardiomyopathy, [28] as well as dilated cardiomyopathy and endocardial fibroelastosis. [29] The diverse functions of alpha-actinin-2 are reflected in the diverse clinical presentation of patients carrying ACTN2 mutations. [30]
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