Cells rely on intricate internal machinery to carry out their many functions. Proteins are the workhorses of this cellular machinery, orchestrating everything from metabolism to movement. Among these proteins, the ARP2/3 complex plays a central role in shaping cells and enabling their movement. It is important for many biological processes.
Understanding the ARP2/3 Complex
The ARP2/3 complex is a protein assembly found in eukaryotic cells, which are cells with a nucleus and other membrane-bound organelles. It consists of seven distinct protein subunits. Two are Actin-Related Proteins, Arp2 and Arp3, which structurally resemble actin. The remaining five subunits, named ARPC1 through ARPC5, associate with Arp2 and Arp3 to form the complete complex.
This multi-subunit complex is primarily located in the cytoplasm, often near the cell membrane, where dynamic changes in cell shape and movement occur. In its inactive state, the Arp2 and Arp3 subunits are separated, preventing them from initiating new actin filaments. Upon receiving specific signals, the complex undergoes a conformational change, activating it. In this active state, Arp2 and Arp3 align to mimic an actin dimer, ready to nucleate a new filament.
How ARP2/3 Drives Cellular Processes
The main function of the ARP2/3 complex is to initiate and branch actin filaments, which are long, thin protein strands forming part of the cell’s internal skeleton, known as the cytoskeleton. The complex achieves this by binding to the side of an existing actin filament, often called a “mother” filament. Once bound, it nucleates a new “daughter” filament at a characteristic 70-degree angle from the mother filament. This process creates a branched, tree-like network of actin filaments.
To become active and perform its branching function, the ARP2/3 complex requires assistance from “activator” proteins, also known as nucleation-promoting factors (NPFs). Proteins from the WASP/N-WASP family are examples of these activators. These activators bind to the ARP2/3 complex, inducing conformational changes that allow Arp2 and Arp3 to initiate new filament growth. This coordinated action allows for the rapid and controlled assembly of branched actin networks, which are important for various cellular activities.
Key Roles in Cell Function
The ARP2/3 complex’s ability to generate branched actin networks allows it to perform many cellular functions. One role is in cell motility, where it drives the formation of sheet-like protrusions called lamellipodia and finger-like extensions known as filopodia. These structures are important for cells to move across surfaces, a process observed in immune cells tracking pathogens or during wound healing. The ARP2/3 complex helps push the cell’s plasma membrane forward, enabling directed movement.
The complex also participates in endocytosis, the process by which cells internalize substances from their external environment. During clathrin-mediated endocytosis, the ARP2/3 complex contributes to forming actin coats around vesicles, helping the plasma membrane invaginate and vesicles pinch off. This function is important for nutrient uptake and receptor recycling at the cell surface.
The ARP2/3 complex is also involved in cell division, specifically during cytokinesis, the physical separation of a cell into two daughter cells. While other proteins contribute, the ARP2/3 complex plays a role in regulating the actin network that forms the contractile ring, which constricts to divide the cytoplasm. Its activity helps maintain the organization of the cortical actin network during this process. The complex also contributes to vesicle trafficking, supporting the movement of membrane-bound sacs within the cell.
ARP2/3’s Impact on Health and Disease
Dysregulation of the ARP2/3 complex or its activators can have significant consequences for human health. Certain bacterial pathogens, such as Listeria monocytogenes, exploit the ARP2/3 complex to move within and between host cells. These bacteria produce a protein called ActA, which mimics host activator proteins, hijacking the ARP2/3 complex to propel themselves using actin polymerization, forming “comet tails” of actin filaments. This manipulation allows the bacteria to spread efficiently throughout infected tissues.
In the context of cancer, altered ARP2/3 activity is frequently observed and can contribute to tumor progression. Many cancers show increased expression of ARP2/3 subunits, which correlates with enhanced cell migration and invasion. The complex promotes the formation of invadopodia, specialized actin-rich protrusions that cancer cells use to degrade the surrounding extracellular matrix, facilitating their spread and metastasis.
Genetic mutations affecting the ARP2/3 complex or its activators can also lead to specific disorders. For instance, mutations in the WASP protein, an activator of ARP2/3, are linked to Wiskott-Aldrich syndrome, a rare X-linked genetic disorder characterized by immune deficiencies. This condition shows the complex’s impact on immune cell function and overall health.