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

Nature Reviews Molecular Cell Biology volume 7, pages 713–726 (2006)Cite this article

Key Points

  • 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.

Abstract

The cellular functions of the actin cytoskeleton require precise regulation of both the initiation of actin polymerization and the organization of the resulting filaments. The actin-related protein-2/3 (ARP2/3) complex is a central player in this regulation. A decade of study has begun to shed light on the molecular mechanisms by which this powerful machine controls the polymerization, organization and recycling of actin-filament networks, both in vitro and in the living cell.

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Figure 1: Structure and function of the ARP2/3 complex.
Figure 2: Model for activation and recycling of the ARP2/3 complex.
Figure 3: Domain organization of nucleation-promoting factors.
Figure 4: Cellular functions of the ARP2/3 complex.
Figure 5: Pathogens use ARP2/3 complex activities during infection.

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Acknowledgements

We thank A. Siripala and K. Campellone for comments on the manuscript, and members of the Welch laboratory for helpful discussion. Research in the Welch laboratory is supported from National Institutes of Health and National Institute of General Medicine Sciences, the National Research Initiative of the United States Department of Agriculture Cooperative State Research, Education and Extension Service, and an Established Investigator Award from the American Heart Association.

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    Erin D. Goley & Matthew D. Welch

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Glossary

Barbed end

(also called the + end). The more dynamic end of the actin filament, where growth and shrinkage are fast. In the actin monomer, the barbed end is on the side of the molecule opposite the nucleotide-binding cleft.

Pointed end

(also called the – end). The less dynamic end of the actin filament. In the actin monomer, the pointed end is on the same side of the molecule as the nucleotide-binding cleft.

FRET

A technique for measuring changes in the distance and orientation between two fluorescent molecules that can be used to monitor protein–protein interactions, or protein conformational dynamics.

Ring canal

Intercellular bridges that connect the developing D. melanogaster oocyte to the nurse cells and serve as conduits for the transfer of cytoplasmic components.

Lamellipodia

Flat, sheet-like cellular protrusions that contain a network of actin filaments that mediate the protrusion of the leading edge of a migrating cell.

Pseudopodia

Large cellular protrusions that contain a network of actin filaments that mediate the protrusion of the leading edge of an amoeboid cell or a phagocyte during crawling migration.

Filopodia

Thin, finger-like structures with a bundled core of actin filaments that form at the leading edge of migrating animal cells.

Fcγ receptor

A family of receptors found on the surface of phagocytic cells. They bind to the constant (Fc) region of immunoglobulins and mediate the phagocytosis of pathogens.

Complement receptor

A family of receptors found on the surface of phagocytic cells. They bind to complement proteins and mediate the phagocytosis of pathogens.

Clathrin-mediated endocytosis

The uptake of material into the cell by a mechanism that involves the assembly of a clathrin protein into a cage-like structure on the cytoplasmic surface of the membrane.

Type III secretion system

A needle-like complex of proteins used by many Gram-negative bacterial pathogens to inject virulence factors (called effectors) directly into the cytoplasm of a host cell.

Antigen-presenting cell

A cell that displays on its surface a foreign antigen in association with a major histocompatibility complex (MHC) protein. Antigen presentation can lead to T-cell activation.

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Goley, E., Welch, M. The ARP2/3 complex: an actin nucleator comes of age. Nat Rev Mol Cell Biol 7, 713–726 (2006). https://doi.org/10.1038/nrm2026

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