Worms have fewer filaments in their muscles when there's too much UNC-45 chaperone (top).

Chaperones protect proteins during their vulnerable folding stages. But too much chaperoning is counterproductive, as it keeps proteins in this vulnerable stage for too long, suggest Landsverk et al. (page 205).

The UNC-45 chaperone protects immature myosin from degradation while it folds into a form compatible with assembly into myofilaments. Without UNC-45, worms have fewer myofilaments in their muscle cells and are, as a result, severely paralyzed. The team now shows, however, that too much UNC-45 also results in myosin degradation, reduced myofilament numbers, and decreased mobility.

Myosin degradation caused by the loss of UNC-45 occurs via ubiquitination-mediated targeting to the proteasome. This same pathway was also the fate of myosin in the presence of too much UNC-45. Inhibiting the proteasome restored myosin levels and worm mobility.

The authors propose that, when there's too much UNC-45, it holds more myosin proteins in their immature, nonmyofilament form. Because most chaperone–substrate interactions are highly dynamic, UNC-45 and myosin are probably constantly binding and releasing. During these moments of release, all this immature myosin would be available for ubiquitination.

Other chaperones have been similarly reported to have optimal concentration ranges. Ensuring that this optimal range is not exceeded might, itself, be achieved by the ubiquitination–proteosome pathway. Indeed, the team has previously shown UNC-45 to be degraded by this route.