Alpha-actinin-2 is a
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respon ...
which in humans is encoded by the ''ACTN2''
gene
In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...
.
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
Titin (contraction for Titan protein) (also called connectin) is a protein that in humans is encoded by the ''TTN'' gene. Titin is a giant protein, greater than 1 µm in length, that functions as a molecular spring that is responsible for t ...
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
The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein or polypeptide), terminated by a free carboxyl group (-COOH). When the protein is ...
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
Dystrophin is a rod-shaped cytoplasmic protein, and a vital part of a protein complex that connects the cytoskeleton of a muscle fiber to the surrounding extracellular matrix through the cell membrane. This complex is variously known as the cos ...
,
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,
,
[ DISC1,]MYOZ1
Myozenin-1 is a protein that in humans is encoded by the ''MYOZ1'' gene.
Interactions
MYOZ1 has been shown to interact with Telethonin, FLNC and Actinin, alpha 2
Alpha-actinin-2 is a protein which in humans is encoded by the ''ACTN2'' gene. Thi ...
,GRIN2B
Glutamate MDAreceptor subunit epsilon-2, also known as ''N''-methyl D-aspartate receptor subtype 2B (NMDAR2B or NR2B), is a protein that in humans is encoded by the ''GRIN2B'' gene.
NMDA receptors
''N''-methyl-D-aspartate (NMDA) receptors are ...
,SYNPO2
Myopodin protein, also called Synaptopodin-2 is a protein that in humans is encoded by the ''SYNPO2'' gene. Myopodin is expressed in cardiac, smooth muscle and skeletal muscle, and localizes to Z-disc structures.
Structure
Myopodin is a 117.4 ...
, LDB3, and FATZ.
Function
The primary function of alpha-actinin-2 is to crosslink filamentous actin molecules and titin
Titin (contraction for Titan protein) (also called connectin) is a protein that in humans is encoded by the ''TTN'' gene. Titin is a giant protein, greater than 1 µm in length, that functions as a molecular spring that is responsible for t ...
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 hypertrophic cardiomyopathy
Hypertrophic cardiomyopathy (HCM, or HOCM when obstructive) is a condition in which the heart becomes thickened without an obvious cause. The parts of the heart most commonly affected are the interventricular septum and the ventricles. This r ...
, as well as dilated cardiomyopathy
Dilated cardiomyopathy (DCM) is a condition in which the heart becomes enlarged and cannot pump blood effectively. Symptoms vary from none to feeling tired, leg swelling, and shortness of breath. It may also result in chest pain or fainting. Co ...
and endocardial fibroelastosis
Endocardial fibroelastosis (EFE) is a rare heart disorder usually occurring in children two years old and younger. It may also be considered a reaction to stress, not necessarily a specific disease.
It should not be confused with endomyocardial f ...
. The diverse functions of alpha-actinin-2 are reflected in the diverse clinical presentation of patients carrying ''ACTN2'' mutations.
References
Further reading
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External links
Mass spectrometry characterization of human ACTN2 at COPaKB
GeneReviews/NIH/NCBI/UW entry on Familial Hypertrophic Cardiomyopathy Overview
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{{Cytoskeletal Proteins
EF-hand-containing proteins