Tropomodulin, best known for its function in the capping of exceptionally long-lived actin filaments in muscle, binds tightly to the minus ends of actin filaments that have been coated and thereby stabilized by tropomyosin. It can also transiently cap pure actin filaments and significantly reduce their elongation and depolymerization rates. A large family of tropomodulin proteins regulates actin filament length and stability in many cell types.
For maximum effect, proteins that bind the side of actin filaments coat the filament completely, and must therefore be present in high amounts. In contrast, end-binding proteins can affect filament dynamics even when they are present at very low levels. Since subunit addition and loss occur primarily at filament ends, one molecule of an end-binding protein per actin filament (roughly one molecule per 200–500 actin subunits) can be enough to transform the architecture of an actin filament network.
Another important mechanism of actin filament regulation depends on proteins that break an actin filament into many smaller filaments, thereby generating a large number of new filament ends. The fate of these new ends depends on the presence of other accessory proteins. Under some conditions, newly formed ends nucleate filament elongation, thereby accelerating the assembly of new filament structures. Under other conditions, severing promotes the depolymerization of old filaments, speeding up the depolymerization rate by tenfold or more. In addition, severing changes the physical and mechanical properties of the cytoplasm: stiff, large bundles and gels become more fluid.
One class of actin-severing proteins is the gelsolin superfamily. These proteins are activated by high levels of cytosolic Ca2+. Gelsolin interacts with the side of the actin filament and contains subdomains that bind to two different sites: one that is exposed on the surface of the filament and one that is hidden between adjacent
Figure 16–18 Profilin and formins. Some members of the formin protein family have unstructured domains or “whiskers” that contain several binding sites for profilin or the profilin–actin complex. These flexible domains serve as a staging area for addition of actin to the growing plus end of the actin filament when formin is bound. Under some conditions, this can enhance the rate of actin filament elongation so that filament growth is faster than that expected for a diffusion-controlled reaction, and faster in the presence of formin and profilin than the rate for pure actin alone (see also Figure 3–78).
Figure 16–17 Actin elongation mediated by formins. Formin proteins (green) form a dimeric complex that can nucleate the formation of a new actin filament (red) and remain associated with the rapidly growing plus end as it elongates. The formin protein maintains its binding to one of the two actin subunits exposed at the plus end as it allows each new subunit to assemble. Only part of the large dimeric formin molecule is shown here. Other regions regulate its activity and link it to particular structures in the cell. Many formins are indirectly connected to the cell plasma membrane and aid the insertional polymerization of the actin filament directly beneath the membrane surface.
continued rapid growth of actin flament at plus end uncapped population of flaments: growth at plus and minus ends capped population of
Figure 16–19 Filament capping and its effects on filament dynamics. A population of uncapped filaments adds and loses subunits at both the plus and minus ends, resulting in rapid growth or shrinkage, depending on the concentration of available free monomers (green line). In the presence of a protein that caps the plus end (red line), only the minus end is able to add or lose subunits; consequently, flaments: growth filament growth will be slower at all at minus end only monomer concentrations above the critical concentration, and filament shrinkage will be slower at all monomer concentrations below the critical concentration. In addition, the critical concentration for the population shifts to that of the filament minus end.