Actinin, alpha 2

Alpha-actinin 2 is a is_associated_with::protein which in humans is encoded by the ACTN2 is_associated_with::gene. 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.

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 is_associated_with::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 is_associated_with::actinins belong to the is_associated_with::spectrin gene superfamily which represents a diverse group of actin-binding cytoskeletal proteins, including is_associated_with::spectrin, is_associated_with::dystrophin, is_associated_with::utrophin and is_associated_with::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 is_associated_with::KCNA5, is_associated_with::DLG1, is_associated_with::DISC1, is_associated_with::MYOZ1, is_associated_with::GRIN2B, is_associated_with::ADAM12, is_associated_with::ACTN3, is_associated_with::MYPN, is_associated_with::PDLIM3, is_associated_with::PKN, is_associated_with::MYOT, is_associated_with::TTN, is_associated_with::NMDAR, is_associated_with::SYNPO2, is_associated_with::LDB3, and is_associated_with::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, Kv1.5 in particular.

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