Untangling Gordian Proteins

Scientists have for the first time found a way to revive proteins damaged by heat or chemicals. The test tube finding, reported in the current Cell, could help explain the formation of prions--the tangled proteins that are implicated in mad cow disease and several human brain disorders--and eventually may lead to a way to smooth out these rogue proteins.

Proteins called chaperones help protect cells from heat and chemicals that cause proteins to lose their shape and clump together. In the test tube, though, chaperones have only been shown to prevent damage, never to repair it. There were hints that a chaperone called heat shock protein 104 (Hsp104) was different: Cell biologist Susan Lindquist of the University of Chicago and her colleagues had shown that yeast lacking Hsp104 couldn't dissolve protein clumps as well as normal controls--suggesting that Hsp104 was needed to untangle gnarled proteins. Still, they couldn't exclude that it was simply preventing the worst tangles from forming.

To show that Hsp104 actively untangles proteins, Lindquist and postdoctoral fellow John Glover conducted test tube experiments with tangled clumps of luciferase, the protein that makes firefly tails glow. When they added purified Hsp104, it failed to liberate more than 5% of the protein. The researchers decided to add to the mix Hsp40 and Hsp70, chaperones that help unfolded proteins take the proper shape and are known to interact with Hsp104. Individually, these two could repair less than 2% of clumped luciferase, but teamed with Hsp104 they brought almost half of the denatured proteins back to life.

Lindquist says Hsp104 may be acting like a molecular crowbar, grabbing on to a tangled protein and then, with the help of the cellular fuel ATP, changing its shape and prying a tangled protein loose. Hsp70 and Hsp40 then could re-fold the freed proteins, she says.

The work "suggests that protein aggregation isn't irreversible," says cell biologist David Smith of the University of Nebraska Medical Center in Omaha. Understanding how cells undo their protein clumps might lead the way to a treatment for diseases that are blamed on tangled proteins, he says, including Creutzfeldt-Jakob disease and Alzheimer's disease.