alphaactinins

Alpha-actinins are a family of actin-binding proteins that crosslink filamentous actin (F-actin) and help organize the cytoskeleton in both muscle and non-muscle cells. They play a key role in forming and maintaining actin networks and in anchoring these networks to membranes and other cytoskeletal elements.

Structurally, alpha-actinins form anti-parallel dimers. Each monomer contains an N-terminal actin-binding domain with two calponin-homology (CH) domains, followed by a central rod domain rich in spectrin repeats that mediates dimerization, and a C-terminal regulatory region that can include a calmodulin-like, EF-hand–containing segment in some isoforms. Dimerization and the arrangement of actin-binding sites enable the crosslinking of actin filaments into networks or bundles, with calcium sensitivity varying by isoform.

In humans, four genes encode alpha-actinins: ACTN1, ACTN2, ACTN3, and ACTN4. ACTN1 and ACTN4 are widely expressed in non-muscle cells, contributing to cortical networks and focal adhesions, while ACTN2 and ACTN3 are enriched in striated muscle, with ACTN2 predominating in cardiac and skeletal muscle Z-discs and ACTN3 associated with fast-twitch muscle fibers. A common ACTN3 polymorphism (R577X) reduces functional alpha-actinin-3 in homozygotes, influencing muscle performance in some individuals.

Functions of alpha-actinins extend to muscle architecture and cell adhesion, where they anchor actin to Z-discs, focal adhesions, and other membrane-associated complexes. They interact with titin and other cytoskeletal or signaling proteins, contributing to mechanotransduction and structural integrity.

Clinical relevance includes links between ACTN gene mutations and musculoskeletal or renal diseases and, in some cases, familial nephrotic syndrome (ACTN4) or thrombocytopenia (ACTN1). Overall, alpha-actinins are essential crosslinkers that shape cellular actin architecture across tissues.