Alpha-actinin-2

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 titin to Z-discs.

ACTN2
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1H8B, 1HCI, 1QUU, 4D1E, 5A37, 5A36, 5A38, 5A4B
Identifiers
Aliases	ACTN2, CMD1AA, CMH23, actinin alpha 2, MYOCOZ, MPD6
External IDs	OMIM: 102573; MGI: 109192; HomoloGene: 31016; GeneCards: ACTN2; OMA:ACTN2 - orthologs
Gene location (Human) Chr. Chromosome 1 (human)[1] Band 1q43 Start 236,664,141 bp[1] End 236,764,631 bp[1]
Gene location (Mouse) Chr. Chromosome 13 (mouse)[2] Band 13 A1|13 4.54 cM Start 12,284,312 bp[2] End 12,355,641 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in Skeletal muscle tissue of rectus abdominis Skeletal muscle tissue of biceps brachii muscle of thigh apex of heart glutes gastrocnemius muscle right ventricle triceps brachii muscle myocardium of left ventricle deltoid muscle Top expressed in soleus muscle ankle myocardium of ventricle extraocular muscle digastric muscle right ventricle cardiac muscles temporal muscle tibialis anterior muscle sternocleidomastoid muscle More reference expression data BioGPS More reference expression data
Gene ontology Molecular function calcium ion binding protein dimerization activity protein homodimerization activity transmembrane transporter binding protein domain specific binding titin Z domain binding LIM domain binding titin binding metal ion binding cytoskeletal protein binding integrin binding actin filament binding protein binding nuclear receptor coactivator activity identical protein binding FATZ binding actin binding phosphatidylinositol-4,5-bisphosphate binding structural constituent of muscle Cellular component cytoplasm cytosol pseudopodium focal adhesion filopodium plasma membrane sarcomere dendritic spine extracellular region Z discdkac cortical actin cytoskeleton actin filament extracellular exosome cytoskeleton platelet alpha granule lumen postsynaptic density membrane glutamatergic synapse postsynaptic density, intracellular component Biological process positive regulation of cation channel activity regulation of apoptotic process muscle contraction positive regulation of potassium ion transport phospholipase C-activating angiotensin-activated signaling pathway cardiac muscle cell development regulation of membrane potential platelet degranulation actin filament uncapping MAPK cascade focal adhesion assembly negative regulation of protein localization to cell surface positive regulation of signaling receptor activity cell adhesion negative regulation of potassium ion transmembrane transporter activity negative regulation of potassium ion transport regulation of nucleic acid-templated transcription microspike assembly positive regulation of endocytic recycling muscle filament sliding protein homotetramerization sarcomere organization positive regulation of potassium ion transmembrane transporter activity protein localization to plasma membrane positive regulation of nucleic acid-templated transcription regulation of NMDA receptor activity Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 88 11472 Ensembl ENSG00000077522 ENSMUSG00000052374 UniProt P35609 Q9JI91 RefSeq (mRNA) NM_001103 NM_001278343 NM_001278344 NM_033268 RefSeq (protein) NP_001094 NP_001265272 NP_001265273 NP_150371 Location (UCSC) Chr 1: 236.66 – 236.76 Mb Chr 13: 12.28 – 12.36 Mb PubMed search [3] [4]
Wikidata
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Structure

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]

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.^[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, K_v1.5 in particular.^[10]

Clinical significance

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]