The ARP2/3 complex: an actin nucleator comes of age

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Abstract
The seven-subunit actin-related proteins-2/3 (ARP2/3) complex is one of three known actin nucleators in eukaryotes, and is unique in its capability to organize filaments into branched networks. The nucleation and branching activities of ARP2/3 are tightly coupled and are regulated by ATP, nucleation-promoting factors (NPFs) and actin. Structural and biochemical data indicate that activation entails a significant conformational change that enables ARP2 and ARP3 to interact as a heterodimer that forms the template for the assembly of a new filament. Over a dozen NPFs have been identified that fall into two classes, based on the mechanism by which they activate the ARP2/3 complex. NPFs differ in domain organization and physiological function and activate ARP2/3 in response to diverse signals. Class I NPFs activate the ARP2/3 complex by promoting a conformational change and presenting an actin monomer, enabling the branching of a new filament. Class II NPFs bind to the ARP2/3 complex and actin filaments and stabilize ARP2/3-mediated branches. Branching by the ARP2/3 complex is crucial for generating actin networks that are ideally suited for force generation. Branching and debranching are regulated in large part by the nucleotide that is bound to ARP2 and also by the nucleotide that is bound to actin subunits in the mother and daughter filaments. The ARP2/3 complex is essential in many, but not all, eukaryotes. It functions during cell motility, phagocytosis, endocytosis, membrane-trafficking events, and cell-type-specific functions such as T-cell activation. The activities of the ARP2/3 complex are exploited during the pathogenesis of a number of infectious agents to initiate actin polymerization that promotes attachment to the host cell, internalization or cell–cell spread. Misregulation of the activities of the ARP2/3 complex are associated with human disease. For example, the X-linked immune disorder Wiskott–Aldrich syndrome results from mutations in the gene that encodes the NPF Wiskott–Aldrich syndrome protein. ARP2/3 complex activity is also associated with metastasis and invasive-cell motility in cancer cells.