Formins

Formins are a family of conserved actin-binding proteins that regulate the nucleation and elongation of actin filaments, thereby shaping the cellular actin cytoskeleton. The core, highly conserved elements of many formins are the FH1 and FH2 domains, which drive actin assembly, with additional regulatory regions such as the diaphanous inhibitory domain (DID) and the diaphanous autoregulatory domain (DAD) that control activity. An N-terminal regulatory region often contains a Rho-binding domain that links formin activity to small GTPases.

Mechanistically, the FH2 domain forms a dimer that nucleates actin filaments and remains associated with the growing barbed end to promote processive elongation. The FH1 domain is rich in proline residues and recruits profilin–actin complexes to accelerate monomer delivery for filament growth. In many diaphanous-related formins (DRFs), autoinhibition is mediated by DID–DAD interactions, which keep the protein inactive until binding of GTP-bound Rho family GTPases releases the autoinhibition and activates the formin.

Formins are widespread across eukaryotes and are classified into broad groups, including diaphanous-related formins (DRFs) such as DIAPH1–3, and non-DRFs that include various FMNL, FHOD, INF2, and related proteins. In plants, formins are categorized into Class I and Class II; in yeast, Bni1 and Bnr1 are two well-studied representatives. Some formins also interact with microtubules, contributing to cross-talk between actin and microtubule networks.

Functions of formins include promoting linear actin filament formation necessary for cytokinesis, cell polarity, migration, filopodia and stress fiber formation, as well as vesicle trafficking and microtubule-associated processes. Due to their central role in cytoskeletal organization, dysregulated formin activity is linked to developmental disorders and disease; pathogenic variants have been associated with platelet disorders, kidney disease, and other conditions, making formins active areas of biomedical research and potential therapeutic targeting.