Actin-related and actin-like proteins: functional diversification of the actin-fold

Actin-related proteins (Arps) and actin-like proteins constitute a subfamily of actin-fold proteins that are evolutionarily and structurally related to conventional actin but functionally distinct. While actin is defined by its ability to form dynamic filaments, bind and hydrolyze ATP, and serve as a major cytoskeletal scaffold, Arps and actin-like proteins have evolved specialized roles in cytoplasmic and nuclear protein complexes. The Arp2/3 complex mediates branched actin nucleation, whereas the dynactin complex, containing Arp1 and Arp11, functions as an activator and cargo-adaptor for dynein-dependent intracellular transport. In the nucleus, multiple Arps, actin, and actin-like proteins are incorporated into large ATP-dependent chromatin-remodelling and histone-modifying complexes, where they regulate nucleosome positioning, histone variant exchange, and transcriptional accessibility. Beyond canonical Arps, mammals encode a range of non-canonical Arps and actin-like proteins, many of which exhibit tissue-specific expression, particularly in the testis, and are associated with spermiogenesis and male fertility. This review summarizes the current knowledge on the classification, structure-function relationship, and cellular roles of human Arps and actin-like proteins, as well as their links to human disease, including immunodeficiency, neurodevelopmental disorders, infertility, and cancer.