A nucleator arms race: cellular control of actin assembly (original) (raw)

2010, Nature Reviews Molecular Cell Biology

For more than a decade the Arp2/3 complex, a handful of nucleation-promoting factors, and formins were the only molecules known to directly nucleate actin filament formation de novo. However, the past several years have brought a surge in the discovery of mammalian proteins with roles in actin nucleation and dynamics. Newly recognized nucleation-promoting factors, such as WASH, WHAMM, and JMY stimulate Arp2/3 complex activity at distinct cellular locations. Formin nucleators with additional biochemical and cellular activities have also been uncovered. Finally, the Spire, Cordon-bleu, and Leiomodin nucleators have revealed new ways of overcoming the kinetic barriers to actin polymerization. Actin is one of the most abundant and highly-conserved proteins in eukaryotic cells, and is structurally related to prokaryotic actin-like proteins, hinting at its ancient evolutionary origins (Box.1). A 42kDa monomeric ATP-binding protein, globular (G)-actin, can undergo cycles of self-assembly into filamentous (F)-actin, ATP hydrolysis, and depolymerization. Actin filaments contain dynamic barbed ends and less active pointed ends that are differentiated by their structural and biochemical characteristics. Filament turnover is controlled by many actinbinding proteins, including some that function in monomer sequestration or delivery, and others that promote filament nucleation, elongation, capping, severing, or depolymerization. The ability of this versatile cytoskeletal system to generate force, create structural scaffolds, and act as tracks for motor proteins makes it a critical participant in numerous cellular functions, including morphogenesis, migration, cytokinesis, and membrane transport (Fig.1). Box 1 The Actin Cytoskeleton: Ancient evolutionary origins and functions Several prokaryotic proteins have structural similarities to eukaryotic actin and assemble into filaments, suggesting that they represent an ancestral actin cytoskeleton. These bacterial factors include MreB (murein formation cluster E B) and ParM (partitioning M) (reviewed in Ref.159; see the figure). MreB is expressed primarily in rod-shaped bacteria, and is an ATPase, similar to eukaryotic actin. Also like actin, MreB subunits are preferentially incorporated into filaments in their ATP-bound form, and depolymerize mainly in the ADPbound form. However unlike F-actin, MreB subunits generally have a non-helical structure, and form short coils, spirals, and ribbons. These filaments help determine bacterial shape by forming a scaffold beneath the inner plasma membrane and positioning enzymes involved in cell wall biosynthesis. Another actin-like bacterial protein, ParM, is encoded on the E.coli R1 plasmid. ParM polymerizes in an ATP-dependent manner to form helical filaments like F-actin, but with the opposite handedness. Moreover, its assembly kinetics are drastically different from eukaryotic actin. ParM spontaneously nucleates more efficiently than actin and might not need nucleation factors. ParM filaments continuously cycle between phases of elongation and rapid catastrophic disassembly, a behavior that was first described for microtubules and is termed dynamic instability. Finally, ParM filaments