So who is PERK and why is he messing with our brains?
PERK is a kinase that spans the membrane of the endoplasmic reticulum. Study the image below. The end of PERK that lives inside the ER lumen is normally bound to a protein called GRP-78, which keeps PERK from being active. If GRP falls off, the cytoplasmic end, which contains the kinase activity, gets turned on, and phosphorylates eIF2α. So what causes this to happen?
It appears that the physiologic role of PERK is to detect the presence of unfolded proteins in the endoplasmic reticulum. Recall that during protein synthesis many nascent proteins are exuded into the ER as they are being translated by the ribosome. This is so that "chaperone" and helper proteins can glom onto the new peptide and help it fold properly, and preliminary packaging and modification of the protein can take place.
If something happens that causes proteins to fold incorrectly, however, you have a serious quality-control problem, and it's time to shut down the whole assembly line until the situation is fixed. That's the job of PERK. Unfolded proteins accumulate in the ER and are "sensed" by GRP-78. When that happens, GRP-78 falls away from PERK, which autophosphorylates and then shuts down translation initiation by phosphorylating eIF2α. This process also activates an elaborate series of events called the unfolded protein response, or UPR, designed to fix the problem.
Feelin' PERKy. PERK Activation by unfolded proteins, which bind to GRP-78 and cause it to fall off the lumenal domain of the kinase, resulting in activation, which leads to eIF2α phosphorylation, which in turn inhibits translation.