mDiaformins

Mammalian diaphanous-related formins, commonly referred to as mDiaformins, are a subfamily of formin proteins that regulate the actin cytoskeleton in mammalian cells. They act as downstream effectors of Rho family GTPases and play key roles in initiating and elongating actin filaments, thereby influencing cell shape, polarity, and movement. The best characterized members are mDia1, mDia2, and mDia3, which are encoded by the DIAPH1–DIAPH3 genes in humans and have conserved functions across mammals.

mDiaformins possess several defining structural features. They contain an N-terminal diaphanous inhibitory domain (DID) that forms an autoinhibitory interaction with the diaphanous autoinhibitory domain (DAD) located further C-terminally. This autoinhibition keeps the protein in an inactive state until signaling relieves it. The N-terminal region also includes a Rho GTPase-binding domain (RBD) that, when engaged by GTP-bound Rho proteins, relieves autoinhibition and activates the formin. The C-terminal portion houses the formin homology 2 (FH2) domain, which directly nucleates actin filaments and processively elongates them, and the formin homology 1 (FH1) domain, which is proline-rich and binds profilin–actin complexes to accelerate filament assembly. A FH3 region contributes to localization and regulation.

Activation of mDiaformins by Rho GTPases promotes the formation of unbranched actin filaments and regulates filament length. In addition to actin polymerization, mDia proteins coordinate with microtubules and participate in processes such as cytokinesis, cell polarization, vesicle trafficking, and neuronal development. Dysregulation of mDiaformin signaling has been linked to various pathological contexts, including impaired cell migration and developmental defects.