Alpha-actinin-2

α-actinin-2 (Actn2) is a member of the spectrin-family of actin crosslinking proteins. It was originally found in skeletal muscle and classified as a muscle type α-actinin. Later, it was also found in the brain at glutamatergic synapses and dendritic spines, thus making the original isoform designations “muscle” or “non-muscle” actinin obsolete. Its structure is the same as that for the other actinins. The N-terminus consists of two highly conserved tandem calponin-homology domains, which are required for actin binding, and are connected to a series of four spectrin-like coiled-coil repeats that make up the rod domain facilitating dimerization of the molecules. Once regarded as simply spacers for actin bundle formation, these spectrin repeats have a newfound role as a docking site or scaffold for many signaling proteins (Djinovic-Carugo et al. 2002). The repeats are followed by a calmodulin-like domain that is composed of two EF hand domains. The EF hands for Actn2 and Actn3 have lost the ability to bind calcium, yet the structures remain evolutionarily conserved which suggests some other major functional role. Its function in skeletal and cardiac and smooth muscle cells is to constitutively anchor the actin filaments at the Z-disks/dense bodies, while in neurons it anchors the NMDA receptor to the cytoskeleton. Actn2 exists as antiparallel homodimers, or it can form heterodimers with Actn3 in type 2B muscle cells (Beggs et al. 1992; Tiso et al. 1999; Mills et al. 2001; Dixson et al. 2003; Otey and Carpen 2004; Virel and Backman 2004).

Unlike Actn1 and Actn4, the EF-hands of Actn2 are incapable of binding Ca²⁺ and are thus calcium-insensitive (Beggs et al. 1992). Its binding is largely constitutive but can be modulated by competitive binding of other proteins. It has been demonstrated that α-actinin dynamics can be regulated by the binding of PtdIns(4,5)P2 to CH2 of the actin-binding domain (Fukami et al. 1992; Fukami et al. 1996; Fraley et al. 2003). PtdIns(4,5)P2 modulates binding to actin, increases the affinity of Actn2 for titin (Young and Gautel. 2000), and inhibits Actn2 binding to CapZ (Papa et al. 1999). In neurons, Actn2 bundling activity has been shown to be enhanced by interaction with rabphillin-3A (Kato et al. 1996) and Actn2 is potentially regulated by phosphorylation at the N-terminus by PKN, which would potentially interfere with actin binding (Mukai et al. 1997).

Aside from binding to F-actin via its actin-binding domain, Actn2 associates with many cellular architecture proteins. At the sarcolemma, Actn2 interacts with affixin (Yamaji et al. 2004), dystrophin (Hance et al. 1999), phospholipase D2 (Park et al. 2000), as well as L-type calcium channels (Sadeghi et al. 2002) and the Kv1.4 and 1.5 potassium channels (Maruoka et al. 2000; Cukovic et al. 2001; Mason et al. 2002). In the z-disk Actn2 interacts with a host of proteins: ADAM12 (Galliano et al. 2000), CapZ (Papa et al. 1999), ENH (Nakagawa et al. 2000; Niederlander et al. 2004), ZASP (Faulkner et al. 1999; Au et al. 2004), calsarcins (Frey et al. 2000; Frey and Olsen. 2002), myopalladin (Bang et al. 2001), elfin (Kotaka et al. 2000), ALP and MLP (Henderson et al. 2003; Klaavuniemi et al. 2004; Mohapatra et al. 2003; Geier et al. 2003; Gehmlich et al. 2004), myotillin (Salmikangas et al. 1999; Salmikangas et al. 2003), FBPase/amorphin complex (Gizak et al. 2003; Rakus et al. 2003; Mamczur et al. 2005), and titin (Sorimachi et al. 1997; Young et al. 1998; Satoh et al. 1999; Atkinson et al. 2000; Atkinson et al. 2000; Luther. 2000;Young and Gautel. 2000; Atkinson et al. 2001; Joseph et al. 2001). In neurons, Actn2 anchors and/or regulates the activity of adenosine A2A (Burgueno et al. 2003) and NMDA receptors (Wyszynski et al. 1997; Wyszynski et al. 1998; Cattabeni et al. 1999; Krupp et al. 1999; Anders et al. 2000; Dunah et al. 2000; Ratzliff and Soltesz. 2001; Leonard et al. 2002; Rycroft and Gibb. 2004) and interacts with and/or is regulated by Rabphillin3A (Kato et al. 1996) and PKN (Mukai et al. 1997). Actn2 has also been reported to interact with GRIP1, glucocorticoid receptor interacting protein 1, in the nucleus (Huang et al. 2004).

No data available.

α-actinin-2 is localized to the Z-disks of muscle cells (Mills et al. 2001; Sorimachi et al. 1997) and to postsynaptic densities and dendritic spines of neurons (Wyszynski et al. 1997).

α-actinin-2 is expressed in all muscle fiber types (Mills et al. 2001; Sorimachi et al. 1997) and in the brain (Wyszynski et al. 1997).

The genetic disease arrhythmogenic right ventricular cardiomyopathy type 2 is linked to a CA4 repeat in the last intron.

No splice variants have been found in mammals.

Mouse monoclonal antibody (mAb) to rabbit skeletal α-actinin, clone EA-53 (Sigma, abcam).

Mouse mAb to chicken gizzard actinin, clone JLN20 (ICN, InnoGenex, BioGenex, Oncogene Research Products).

Bovine mAb to mouse actinin, clone BM-75.2 (Sigma, ICN).

Mouse mAb to human actinin, clone AT 6/172 (Research Diagnostics Inc, Immune Systems Ltd).

Mouse mAb to quail smooth muscle actinin, 1E12 (Developmental Studies Hybridoma Bank at the University of Iowa).

Mouse mAb to chicken gizzard, clone CB11 (ICN, Affiniti).

Rabbit polyclonal Ab to chicken gizzard (ICN).

Mouse mAb to human red blood cell ghosts, clone RBC2/1B6 (Novocastra).

Mouse mAb to smooth muscle actinin, clone 1A4 (Diagnostic BioSystems).

Goat polyclonal Ab to amino terminus of human ACTN1, N-19 (Santa Cruz Biotechnology).

Goat polyclonal Ab to human ACTN1 carboxy terminus, C-20 (Santa Cruz Biotechnology).