Actinin alpha 2

Structure

Alpha-actinin 2 is a 103.8 kDa protein composed of 894 amino acids. 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. The high-resolution crystal structure of human alpha-actinin 2 at 3.5 Å was recently resolved. Alpha actinins belong to the spectrin gene superfamily which represents a diverse group of actin-binding cytoskeletal proteins, including spectrin, dystrophin, utrophin and fimbrin. 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, DLG1, DISC1, MYOZ1, GRIN2B, ADAM12, ACTN3, MYPN, PDLIM3, PKN, MYOT, TTN, NMDAR, SYNPO2, LDB3, and FATZ.

Function

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. 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. 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.

Clinical significance

Mutations in ACTN2 are associated with hypertrophic cardiomyopathy, as well as dilated cardiomyopathy and endocardial fibroelastosis. The diverse functions of alpha-actinin 2 are reflected in the diverse clinical presentation of patients carrying ACTN2 mutations.