“Last hired, first fired” is the rule when businesses are laying off workers. As Medicherla and Goldberg show, cells follow a similar strategy when weeding out damaged proteins, eliminating the freshly manufactured molecules.

Defective proteins, such as those induced by heat or reactive oxygen species, are a threat. Clumps of them build up in Parkinson's disease, Alzheimer's disease, and other illnesses. One way that cells get rid of faulty proteins is by feeding them into a molecular garbage disposal system called the ubiquitin–proteasome pathway. What researchers didn't know was whether certain types of proteins were more susceptible to damage and more likely to get trashed.

To find out, Medicherla and Goldberg warmed yeast cells to deform their proteins. In these cells protein breakdown surged, but surprisingly it tailed off after about an hour. The researchers determined that during this time the cells were demolishing newly made proteins, not established ones. The scientists saw similar discrimination against youthful proteins when they treated the cells to spur production of reactive oxygen species. Older proteins escaped destruction even though they incurred damage.

The results indicate that young proteins pass through a vulnerable stage that lasts around an hour. Folding into shape would probably take a few minutes at most, say the authors. But the proteins might also have to join with other proteins to form complexes, undergo structural modifications, or move to their home in the cell, during which time they are prone to damage and thus to destruction.

Medicherla, B., and A.L. Goldberg.
J. Cell Biol.