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 titintoZ-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]
PDB gallery
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1h8b: EF-HANDS 3,4 FROM ALPHA-ACTININ / Z-REPEAT 7 FROM TITIN
1hci: CRYSTAL STRUCTURE OF THE ROD DOMAIN OF ALPHA-ACTININ
1quu: CRYSTAL STRUCTURE OF TWO CENTRAL SPECTRIN-LIKE REPEATS FROM ALPHA-ACTININ
1tjt: X-ray structure of the human alpha-actinin isoform 3 at 2.2A resolution
1wku: High resolution structure of the human alpha-actinin isoform 3
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Proteins of the cytoskeleton
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See also: cytoskeletal defects |