Alpha-actinin-2 is a
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...
which in humans is encoded by the ''ACTN2''
gene
In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...
.
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 (; also called connectin) is a protein that in humans is encoded by the ''TTN'' gene. The protein, which is over 1 μm in length, functions as a molecular spring that is responsible for the passive elasticity of muscle. It comprises 2 ...
to
Z-disc
A sarcomere (Greek σάρξ ''sarx'' "flesh", μέρος ''meros'' "part") is the smallest functional unit of striated muscle tissue. It is the repeating unit between two Z-lines. Skeletal muscles are composed of tubular muscle cells (called muscl ...
s.
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
The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the amin ...
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, carboxy 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 t ...
EF hand
The EF hand is a helix–loop–helix structural domain or ''motif'' found in a large family of calcium-binding proteins.
The EF-hand motif contains a helix–loop–helix topology, much like the spread thumb and forefinger of the human hand, in ...
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
actinin
Actinin is a microfilament protein. The functional protein is an anti-parallel dimer, which cross-links the thin filaments in adjacent sarcomeres, and therefore coordinates contractions between sarcomeres in the horizontal axis. Alpha-actinin is ...
s belong to the
spectrin
Spectrin is a cytoskeletal protein that lines the intracellular side of the plasma membrane in eukaryotic cells. Spectrin forms pentagonal or hexagonal arrangements, forming a scaffold and playing an important role in maintenance of plasma mem ...
gene superfamily which represents a diverse group of actin-binding
cytoskeletal
The cytoskeleton is a complex, dynamic network of interlinking protein filaments present in the cytoplasm of all Cell (biology), cells, including those of bacteria and archaea. In eukaryotes, it extends from the cell nucleus to the cell membrane ...
proteins, including
spectrin
Spectrin is a cytoskeletal protein that lines the intracellular side of the plasma membrane in eukaryotic cells. Spectrin forms pentagonal or hexagonal arrangements, forming a scaffold and playing an important role in maintenance of plasma mem ...
,
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 costa ...
,
utrophin and
fimbrin
Fimbrin also known as is plastin 1 is a protein that in humans is encoded by the PLS1 gene. Fimbrin is an actin cross-linking protein important in the formation of filopodia.
Structure
Fimbrin belongs to the calponin homology (CH) domain sup ...
.
Skeletal, cardiac, and smooth muscle isoforms are localized to the
Z-disc
A sarcomere (Greek σάρξ ''sarx'' "flesh", μέρος ''meros'' "part") is the smallest functional unit of striated muscle tissue. It is the repeating unit between two Z-lines. Skeletal muscles are composed of tubular muscle cells (called muscl ...
and analogous dense bodies, where they help anchor the myofibrillar actin filaments. Alpha-actinin 2 has been shown to
interact with
KCNA5,
,
[ ]DISC1
Disrupted in schizophrenia 1 is a protein that in humans is encoded by the ''DISC1'' gene. In coordination with a wide array of interacting partners, DISC1 has been shown to participate in the regulation of cell proliferation, differentiation, ...
,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 ...
,ADAM12
Disintegrin and metalloproteinase domain-containing protein 12 (previously Meltrin) is an enzyme that in humans is encoded by the ''ADAM12'' gene. ADAM12 has two splice variants: ADAM12-L, the long form, has a transmembrane region and ADAM12-S, ...
, ACTN3
Alpha-actinin-3, also known as alpha-actinin skeletal muscle isoform 3 or F-actin cross-linking protein, is a protein that in humans is encoded by the ''ACTN3'' gene (named sprinter gene, speed gene or athlete gene) located on chromosome 11. All ...
,NMDAR
The ''N''-methyl-D-aspartate receptor (also known as the NMDA receptor or NMDAR), is a glutamate receptor and predominantly Ca2+ ion channel found in neurons. The NMDA receptor is one of three types of ionotropic glutamate receptors, the othe ...
, SYNPO2, LDB3, and FATZ.
Function
The primary function of alpha-actinin-2 is to crosslink filamentous actin molecules and titin
Titin (; also called connectin) is a protein that in humans is encoded by the ''TTN'' gene. The protein, which is over 1 μm in length, functions as a molecular spring that is responsible for the passive elasticity of muscle. It comprises 2 ...
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 muscle tissues of the heart become thickened without an obvious cause. The parts of the heart most commonly affected are the interventricular septum and the ...
, 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. C ...
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