Alpha-actinin-2

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, K_v1.5 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]