Disease relevance of ACTN2

• This will enable mutation screening in patients affected with hereditary diseases linked to the marker CA4F/R, a polymorphism in the last intron of the alpha-actinin-2 gene [1].

High impact information on ACTN2

• Here, we report the identification and characterization of a new skeletal muscle protein containing a PDZ domain that binds to the COOH-terminal region of alpha-actinin-2 [2].
• ALP is not a component of the dystrophin complex, but occurs in association with alpha-actinin-2 at the Z lines of myofibers [3].
• The absence of a disease phenotype secondary to alpha-actinin-3 deficiency is likely due to compensation by the homologous protein, alpha-actinin-2 [4].
• We have solved the solution structure of a complex between the calcium-insensitive C-terminal EF-hand domain of alpha-actinin-2 and the seventh Z-repeat of titin [5].
• Like Ca(2+)/calmodulin, autophosphorylated CaMKII competes with alpha-actinin-2 for binding to NR1 [6].

Biological context of ACTN2

• As with other muscle-specific isoforms, the EF-hand domains in ACTN2 and ACTN3 are predicted to be incapable of binding calcium, suggesting that actin binding is not calcium sensitive [7].
• ACTN2 was mapped to human chromosome 1q42-q43 and ACTN3 to 11q13-q14 by somatic cell hybrid panels and fluorescent in situ hybridization [7].
• A (CA)n repeat polymorphism for the human skeletal muscle alpha-actinin gene ACTN2 and its localization on the linkage map of chromosome 1 [8].
• A CA dinucleotide repeat polymorphism has been identified for the skeletal muscle alpha-actinin gene ACTN2 [8].
• A series of intronic primers was specifically designed and produced, to amplify all the exons of ACTN2, directly from genomic DNA [1].

Anatomical context of ACTN2

• Northern blot analysis demonstrated that ACTN2 is expressed in both skeletal and cardiac muscle, but ACTN3 expression is limited to skeletal muscle [7].
• We studied expression of the skeletal muscle isoforms of alpha-actinin (alpha-actinin-2 and alpha-actinin-3) in muscle biopsies from 12 patients with pure CMD (including one with a merosin abnormality), two with unclassified CMD and central nervous system (CNS) involvement, and three with other neuromuscular disorders [9].
• The ion channels and alpha-actinin-2 co-localize at the membrane in HEK cells, where disruption of the actin cytoskeleton and antisense constructs to alpha-actinin-2 modulate the ion and gating current density [10].
• Fine mapping and genomic structure of ACTN2, the human gene coding for the sarcomeric isoform of alpha-actinin-2, expressed in skeletal and cardiac muscle [1].
• Drebrin A and alpha-actinin-2 are two major actin-binding proteins in dendritic spines [11].

Associations of ACTN2 with chemical compounds

• Reduced ethanol inhibition of N-methyl-D-aspartate receptors by deletion of the NR1 C0 domain or overexpression of alpha-actinin-2 proteins [12].

Physical interactions of ACTN2

• Additional clustering of NMDA receptors is provided through the binding of NRI subunits to the cytoskeletal protein alpha-actinin-2 [13].
• The alpha-actinin-2 binding site of the Z-disc titin is located within a sequence of 45-residue repeats, referred to as Z-repeat region [14].
• ZASP PDZ structure was used to model other members of the enigma family by homology and to predict their abilities to bind alpha-actinin-2 [15].

Other interactions of ACTN2

• We used linkage analysis with polymorphic CA repeats to test for the involvement of two candidate loci, APOA2 and ACTN2 [16].
• Interaction of hCLIM1, an enigma family protein, with alpha-actinin 2 [17].
• Here, using a yeast two-hybrid approach, we have identified the F-actin cross-linking protein filamin as a ligand for the caveolae-associated protein caveolin-1 [18].
• We have determined the structure of ZASP PDZ by NMR and showed that it is a classical class 1 PDZ domain that recognizes the carboxy-terminal sequence of an alpha-actinin-2 calmodulin-like domain with micromolar affinity [15].
• Furthermore, this modulation showed remarkable preference for NMDA receptor inactivation mediated by alpha-actinin-2 [19].

Analytical, diagnostic and therapeutic context of ACTN2

• Analysis in cell culture systems demonstrated that the mutation abolishes the interaction between MLP and alpha-actinin-2 and the cellular localization of MLP was altered [20].
• Using a human muscle frozen section with an area of 4800 microm2 as a model target, we successfully selected monoclonal antibody fragments directed against three major (myosin heavy chain, actin, and tropomyosin-alpha) and one minor (alpha-actinin 2) muscle constituent proteins [21].
• Three genes, NOS3, alpha-actinin-2 and alpha-catenin, suspected of playing a role in tumor genesis, were explored by quantitative RT-PCR analysis and immunohistochemistry [22].
• To address this issue, we expressed both alpha-actinin-2 and -3 in vitro and were able to detect their interaction by both blot overlay and co-immunoprecipitation methods [23].

References