Actinin

Actinin is a family of actin-binding proteins that organize the actin cytoskeleton by crosslinking filaments into networks and bundles. Members share an N-terminal actin-binding domain composed of two calponin-homology (CH) folds, a central rod domain of spectrin repeats that promotes dimerization, and a C-terminal tail with EF-hand calcium-binding motifs that regulate activity in some isoforms. Alpha-actinin proteins form parallel or antiparallel dimers that bridge actin filaments and connect to other structural elements.

In humans, four genes encode actinin isoforms: ACTN1 (non-muscle), ACTN2 and ACTN3 (muscle-specific), and ACTN4 (ubiquitously expressed). In muscle, alpha-actinins localize to the Z-disc, crosslinking thin filaments and anchoring the sarcomere to adjacent structural proteins. In non-muscle cells they organize cortical actin networks, stress fibers, and focal adhesions, thereby contributing to cell shape, adhesion, and motility. Actinin interacts with a range of partners, including titin at sarcomeric Z-discs and other actin-associated proteins, linking the cytoskeleton to membranes and adhesion complexes.

Regulation can be calcium-sensitive in some isoforms because of EF-hand motifs, allowing Ca2+-dependent modulation of actin binding and crosslinking in certain contexts. Genetic variation in ACTN genes influences physiology; for example, ACTN3 carries a common R577X nonsense variant that abolishes functional protein in a substantial fraction of the population and is associated with differences in sprint versus endurance performance. Mutations in ACTN2 and ACTN4 have been linked to cardiomyopathies and familial kidney disease, respectively.

Actinin is highly conserved across eukaryotes and plays a central role in organizing the actin cytoskeleton in diverse cell types.