2011 Lasker Prize Awarded for Discoveries in Protein Folding
BioWorld Today Science Editor
Science awards season kicked off Monday with the announcement that the 2011 Albert Lasker Basic Medical Research Award went jointly to Ulrich Hartl, of the German Max-Planck Institute for Biochemistry, and Arthur Horwich, of Yale University.
Hartl and Horwich discovered so-called chaperone proteins, which help other proteins fold correctly. And in doing so, they ultimately changed the scientific view of homeostasis, or the balance between folded and unfolded proteins.
In a video interview posted to the Lasker Foundation website, Nobelist Guenther Blobel said that Hartl's and Horwich's discoveries "made people think in a different way. And that's what science is all about."
When the two researchers began looking at how proteins get into their three-dimensional shape, the question of how they fold into that shape actually seemed pretty settled. Biochemist Christian Anfinsen had won the 1972 Nobel Prize in chemistry for showing that a protein's three-dimensional shape is dependent only on its amino acid sequence, and that in a test tube, isolated proteins can and will fold into their correct shape without any help.
However, Horwich told BioWorld Today, several things suggested even at the time that in an actual cell, things might be a bit more complicated.
For one thing, "even in Anfinsen's original experiments, the folding was pretty slow," whereas in cells, protein folding can clearly change within minutes in response to changes in the environment. And such speedy folding occurs despite the fact that in the crowded conditions of a living cell, folding should, if anything, proceed more slowly than in a test tube.
For another, so-called heat shock proteins had already been identified as a sort of "molecular crowbar" that could pull apart proteins if they clumped together when a cell was under stress.
"All these things were sort of in front of us," Horwich said. And so, Horwich, Hartl and their colleagues began to wonder whether cellular aids for protein folding "go to a further level," beyond the stress response.
Anfinsen himself, Horwich said, had wondered the same thing. But "he couldn't figure out what the common feature [of unfolded proteins] would be." (That feature would ultimately turn out to be hydrophobic amino acids, which are normally buried in the core of a folded protein to keep them away from the watery environment of the cell's interior. Chaperone proteins can recognize such hydrophobic amino acids and bind to them, helping proteins fold into their correct shape.)
The researchers began by looking at mitochondrial proteins. Those proteins, Horwich said, clearly go through the membrane unfolded. "Do they then spontaneously refold . . . or could there be assistance?"
Searching for such assistance in yeast, the researchers ultimately identified the protein chaperonin. Chaperonin consists of two subunits, GroEL and GroES, that work together to form what co-winner Ulrich Hartl described as a sort of container.
The container consists of a vessel that can isolate a protein and give it the space it needs to fold properly, and a lid. "Only when the lid binds does the vessel expand and allow the protein to fold in this space," Hartl said. Later work showed that chaperonin was identical to a stress response protein, showing up the idea that many of the same mechanisms help proteins fold under normal and extraordinary conditions.
Hartl said the team spent much of its time dotting its i's and crossing its t's on the experimental evidence: "There was considerable resistance against the idea that the folding of a protein would require a cellular machinery, so we had to have really strong data."
Today, protein folding is recognized as a third step that is almost on a par with transcription and translation in its importance for keeping cells running.
"If you delete the chaperones from cells, they're dead immediately," Horwich said, because any protein that is longer than about 100 amino acids is unlikely to fold up correctly on its own.
Improper protein folding is now also recognized as being behind many diseases. The same hydrophobic amino acids that allow chaperone proteins to recognize unfolded proteins will make those proteins aggregate, or clump. Clumps that appear to be particularly toxic for neurons, from amyloid plaques on, are a feature of many neurodegenerative disorders.
Hartl is chairman of the scientific advisory board of Cambridge, Mass.-based biopharmaceutical company Proteostasis Therapeutics. (See BioWorld Today, Dec. 11, 2009.)
That company, Hartl told BioWorld Today, is "looking for ways to up-regulate the cellular chaperone capacity to prevent the aggregation of proteins."
Proteostasis has yet to make it into the clinic. But Horwich, who studies the contribution of SOD-1 clumps to Lou Gehrig's disease, shares Hartl's belief that the work paves the way for useful clinical strategies. A full understanding of how proteins fold, and how the process can go awry, would most likely lead to new strategies to prevent aggregation. And with that, "we might really be able to forestall clinical disease."
The Lasker Foundation also announced that Youyou Tu won the 2011 Lasker DeBakey Clinical Medical Research Award for her discovery of the antimalarial drug artemisinin. The Lasker Bloomberg public service award went to the National Institutes of Health clinical center.
Published: September 13, 2011
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