Figure 6.

Model for decreased traction force generation and increased talin accumulation after talin rod domain destabilization. Talin is recruited into nascent adhesions in its autoinhibited conformation and in the absence of mechanical load. Other adhesion proteins participating in the recruitment of talin are omitted from the schematic representation for simplicity. During adhesion maturation, mechanical forces transmitted through the talin rod domain promote unfolding of the rod subdomains. Subdomain unfolding exposes cryptic VBSs and allows vinculin binding. Destabilized talin R3 subdomains unfold at lower force, facilitating subdomain unfolding and vinculin binding. Talin rod subdomain unfolding and vinculin binding initiate negative feedback loops that limit cellular traction force generation and adhesion growth. Decreased unfolding force of the destabilized talin rod R3 subdomain results in the activation of this negative feedback also in adhesions transmitting low magnitude forces, which decreases overall traction force generation. In mature focal adhesions, talin rod subdomains unfold at their characteristic threshold forces, creating a heterogeneous pool of talin molecules with rod subdomains unfolded to various degrees. Together with the decrease in cellular traction force generation, the intense accumulation of destabilized talin proteins into focal adhesions results in a large decrease in the force transmitted by an individual talin protein, which increases the mobility of talin proteins within focal adhesions. Decreased traction force generation also affects the unfolding of other talin rod domain bundles, which results in a decrease in the vinculin/talin ratio in these adhesions.