Within every living cell is a dynamic world maintained by an internal structure called the cytoskeleton. This network of protein filaments provides shape, enables movement, and manages cell division. The assembly of this cellular skeleton falls to specialized proteins that act as molecular construction workers. Among the most prominent of these are the formin proteins.
Defining Formin Proteins
Formin proteins are a large and diverse family of proteins found in nearly all eukaryotic organisms, from single-celled yeast to complex mammals. Their central function is to act as regulators of actin, a protein that serves as the fundamental building block for many cytoskeletal structures. If actin proteins are the “bricks” of the cellular skeleton, formins are the specialized machines that lay these bricks down, guiding the growth of long, straight chains called actin filaments.
All formins share a modular structure, but their activity is driven by two functional regions known as formin homology (FH) domains. The Formin Homology 2 (FH2) domain is the core of the machine, forming a donut-shaped ring that encircles the growing end of an actin filament.
Working in concert with the FH2 domain is the Formin Homology 1 (FH1) domain. The FH1 domain can be pictured as a set of long, flexible arms rich in proline that capture profilin, a protein that carries individual actin monomers, to speed up construction.
The Mechanism of Actin Assembly
Formins build actin filaments in a highly controlled, two-step operation involving nucleation and elongation. This mechanism allows cells to rapidly construct straight, unbranched actin filaments precisely where and when they are needed for specific tasks.
The first step is nucleation, the act of starting a new filament. Individual actin monomers are unstable on their own, so the ring-like FH2 domain captures and stabilizes two or three of them, creating a stable foundation from which a new filament can grow.
Once a nucleus is formed, the formin transitions to the elongation phase. The FH2 domain remains firmly attached to the fast-growing end of the new filament, a position known as the barbed end. It moves processively, stepping onto the newest actin subunit as it is added, which guides the filament’s growth in a straight line and protects the end from “capping” proteins that would otherwise halt elongation.
While the FH2 domain manages the filament end, the FH1 domain works to accelerate the growth rate. Its flexible, proline-rich arms continuously capture profilin-actin complexes from the cellular environment. These captured complexes are then efficiently delivered to the FH2 domain, which facilitates their addition to the growing filament, increasing the rate of elongation significantly.
Essential Cellular Processes
The ability of formins to assemble long actin filaments underpins some of the most fundamental activities of a cell. Cells rely on the structural support and mechanical force generated by formin-built actin networks for division, migration, and maintaining internal architecture.
One example of formin function occurs during cytokinesis, the final step of cell division. To separate one cell into two, the cell builds a contractile ring of actin and myosin filaments at its equator. Formins are responsible for assembling the linear actin filaments that make up this ring, and as the ring tightens, it constricts the cell membrane to pinch the cell in two.
Cell migration, used by immune cells to reach infections or by skin cells to heal a wound, also relies on formin activity. To move, a cell must extend protrusions in the direction of travel. Formins build actin-rich structures called filopodia, which are thin, finger-like extensions that act as cellular sensors, providing the rigid support needed to push the cell membrane forward.
Beyond these dynamic events, formins also contribute to maintaining a cell’s internal architecture. They help establish and maintain cell polarity, which is the cell’s ability to distinguish “front” from “back” or “top” from “bottom.” This organization is necessary for everything from nutrient absorption in intestinal cells to the proper transmission of signals in nerve cells, as formins create stable internal tracks that organize the cell’s contents.
Connection to Human Disease
Because formins direct such basic cellular activities, errors in their function are linked to a wide range of human diseases, from genetic disorders to cancer.
The role of formins in cell migration is significant in the context of cancer metastasis. Metastasis is the process by which cancer cells break away from their original site, travel through the body, and establish new tumors in distant organs. This invasive behavior requires a high degree of cell motility, and cancer cells can upregulate formin activity to enhance their ability to move and invade surrounding tissues.
Mutations in the genes that provide instructions for making formin proteins are the direct cause of several inherited disorders. For example, mutations in the INF2 gene are a leading cause of a kidney disease called focal segmental glomerulosclerosis (FSGS). Alterations in other formin genes, such as DIAPH1, have been linked to sensorineural hearing loss, while mutations in FMN2 are associated with intellectual disability. These conditions arise because cells in the affected tissues cannot properly form their shape due to faulty actin assembly.
The proper function of the immune system also depends on formins. Immune cells, such as neutrophils, must be able to migrate quickly from the bloodstream to sites of infection to fight off pathogens. If the formin proteins in these immune cells are defective, their ability to move is impaired, weakening the body’s ability to mount an effective defense against infections.