Arp2/3 complex

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File:Arp2 3 complex.png
Atomic structure of bovine Arp2/3 complex [1] (PDB code: 1k8k). Color coding for subunits: Arp3, orange; Arp2, marine (subunits 1 & 2 not resolved and thus not shown); p40, green; p34, ice blue; p20, dark blue; p21, magenta; p16, yellow.

Arp2/3 complex is a seven-subunit protein that plays a major role in the regulation of the actin cytoskeleton. Two of its subunits, the Actin-Related Proteins ARP2 and ARP3 closely resemble the structure of monomeric actin and serve as nucleation sites for new actin filaments. The complex binds to the sides of existing ("mother") filaments and initiates growth of a new ("daughter") filament at a distinctive 70 degree angle from the mother. Branched actin networks are created as a result of this nucleation of new filaments. The regulation of rearrangements of the actin cytoskeleton is important for processes like cell locomotion, phagocytosis, and intracellular motility of lipid vesicles.

The Arp2/3 complex was first identified in Acanthamoeba castellanii and has since been found in every eukaryotic organism studied.

Mechanisms of actin polymerization by Arp2/3

File:Arp23 side branching model.png
Side branching model of the Arp2/3 complex. Activated Arp2/3 complex binds to the side of a "mother" actin filament. Both Arp2 and Arp3 form the first two subunits in the new "daughter" filament.
File:Arp23 barbed end branching model.png
Barbed end branching model of the Arp2/3 complex. Activated Arp2/3 competes with capping proteins to bind to the barbed end of an actin filament. Arp2 remains bound to the mother filament, while Arp3 is outside. The two Arp subunits form the first subunits of each branch and the two branches continue to grow by addition of G-actin to each Arp

Many actin-related molecules create a free barbed end for polymerization by uncapping or severing pre-existing filaments and using these as nucleation cores. However, the Arp2/3 complex stimulates actin polymerization by creating a new nucleation core. The nucleation core activity of Arp2/3 is activated by members of the Wiskott-Aldrich syndrome family protein (WASP, N-WASP, and WAVE proteins). The V domain of a WASP protein interacts with actin monomers while the CA region associates with the Arp2/3 complex to create a nucleation core. However, de novo nucleation followed by polymerization is not sufficient to form integrated actin networks, since these newly synthesized polymers would not be associated with pre-existing filaments. Thus, the Arp2/3 complex binds to pre-existing filaments so that the new filaments can grow on the old ones and form a functional actin cytoskeleton.[2] Capping proteins limit actin polymerization to the region activated by the Arp2/3 complex, and the elongated filament ends are recapped to prevent depolymerization and thus conserve the actin filament.[3]

The Arp2/3 complex simultaneously controls nucleation of actin polymerization and branching of filaments. Moreover, autocatalysis is observed during Arp2/3-mediated actin polymerization. In this process, the newly formed filaments activate other Arp2/3 complexes, facilitating the formation of branched filaments.

The mechanisms of actin polymerization by Arp2/3 has been the subject of dispute in the recent years. The question is where the complex binds the filament and how it nucleates a "daughter" filament. Historically two models have been proposed to describe the formation of branched filaments:

Side branching model

In the side [4][12] provides strong support for this model.

Barbed end branching model

In the barbed end branching model, Arp2/3 associates at the barbed end of growing filaments, allowing for the elongation of the original filament and the formation of a branched filament,[2] suggesting that branching is induced with Arp2 and Arp3 being incorporated in two different actin filaments. This model is only based on kinetic analysis and has no support from structural data whatsoever.

Cellular uses of Arp2/3

The Arp2/3 complex appears to be important in a variety of specialized cell functions that involve the actin cytoskeleton. The complex is found in cellular regions characterized by dynamic actin filament activity; in macropinocytotic cups, in the leading edge of motile cells (lamellipodia), and in motile actin patches in yeast.[8] In mammals and the social amoeba Dictyostelium discoideum [9] [10] it is required for phagocytosis. The complex has also been shown to be involved in the establishment of cell polarity and the migration of fibroblast monolayers in a wound-healing model.[11] Moreover, enteropathogenic organisms like Listeria monocytogenes and Shigella use the Arp2/3 complex for actin-polymerization dependent rocketing movements. The Arp2/3 complex also regulates the intracellular motility of endosomes, lysosomes, pinocytic vesicles and mitochondria.[6] Moreover, recent studies show that the Arp2/3 complex is essential for proper polar cell expansion in plants. Arp2/3 mutations in Arabidopsis result in abnormal filament organization, which in turn affects the expansion of trichomes, pavement cells, hypocotyl cells, and root hair cells.[5][7]

References

  1. a  Robinson RC, Turbedsky K, Kaiser DA, Marchand JB, Higgs HN, Choe S, Pollard TD. (2001) Crystal structure of Arp2/3 complex. Science 294(5547):1679-84. Entrez PubMed 11721045
  2. a b  Suetsugu, S., Miki, H., and Takenawa, T. (2002) Spatial and temporal regulation of actin polymerization for cytoskeleton formation through Arp2/3 complex and WASP/WAVE proteins. Cell Motility and the Cytoskeleton 51: 113-122. Entrez PubMed 11921168
  3. a  Aguda, A., Burtnick, L., and Robinson, R. (2005) The state of the filament. EMBO reports 6: 220-226. Entrez PubMed 15741975
  4. a  Egile C., Rouiller I., Xu X., Volkmann N., Li R., Hanein D. (2005) Mechanism of Filament Nucleation and Branch Stability Revealed by the Structure of the Arp2/3 Complex at Actin Branch Junctions. PLoS BIOLOGY Vol. 3, 1902 (11) 1902-09 Entrez PubMed 16262445
  5. a  Bannigan, A. and Baskin, T. (2005) Directional cell expansion--turning toward actin. Current Opinion in Plant Biology 8: 619-624. Entrez PubMed 16181803
  6. a  Mathur, J. (2005) BioEssays 27: 377-387. Entrez PubMed 15770684
  7. a  Xu, J. and Scheres, B. (2005) Cell polarity: ROPing the ends together. Current Opinion in Plant Biology 8: 613-618. Entrez PubMed 16182602
  8. a  Warren, D. T., Andrews, P. D., Gourlay, C. W. and Ayscough, K. R. (2002) Sla1p couples the yeast endocytic machinery to proteins regulating actin dynamics. J. Cell Sci. 115, 1703–1715 Entrez PubMed 11950888
  9. a  May, R. C., Caron, E., Hall, A. and Machesky, L. M. (2000) Involvement of the Arp2/3 complex in phagocytosis mediated by FcγR or CR3. Nat. Cell Biol. 2, 246–248 Entrez PubMed 10783245
  10. a  Insall, R., Muller-Taubenberger, A., Machesky, L., Kohler, J., Simmeth, E., Atkinson, S. J., Weber, I. and Gerisch, G. (2001) Dynamics of the Dictyostelium Arp2/3 complex in endocytosis, cytokinesis, and chemotaxis. Cell Motil. Cytoskeleton 50, 115–128 Entrez PubMed 11807934
  11. a  Magdalena, J., Millard, T. H., Etienne-Manneville, S., Launay, S., Warwick, H. K. and Machesky, L. M. (2003) Involvement of the arp2/3 complex and scar2 in Golgi polarity in scratch wound models. Mol. Biol. Cell 14, 670–684 Entrez PubMed 12589062
  12. a  Volkmann N., Amann K.J., Stoilova-McPhie S., Egile C., Winter D.C., Hazelwood L., Heuser J.E., Li R., Pollard T.D., Hanein D. (2001) Structure of Arp2/3 complex in its activated state and in actin filament branch junctions. Science 293, 2456-2459 Entrez PubMed 11533442

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