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September 22, 2011
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Forensic Chemistry: A new method could increase the number of explosives detected by airport screeners.
Trade: U.S. companies complain of market dumping by China.
Layoffs follow similar moves by Amgen, AstraZeneca.
Environment: Ban to halt export of hazardous waste to developing world.
Penrose (Parney) Albright will direct DOE national lab.
Toxic Exposure: Mercury isotopes in human hair illuminate dietary and industrial sources.
Cancer Biochemistry: Mass spectrometry follows the metabolism of very long fatty acids in cancer cells.
A claw-like molecule can unravel the aberrant protein snarls behind diseases such as Alzheimer's and Parkinson's, possibly serving as a new strategy to treat a broad range of protein-misfolding diseases (J. Am. Chem. Soc., DOI: 10.1021/ja206279b).
Amyloids, the protein clumps associated with these diseases, form when normal proteins in the cell go bad: They unfold and then stick together in aggregates that can damage cells. Previous research on amyloids suggests the amino acid lysine in proteins acts as an amyloid glue. Lysine's long alkane chain and terminal amine group can form both hydrophobic and electrostatic interactions, two forces that drive protein aggregation.
So when Gal Bitan of the University of California, Los Angeles, read a study describing a molecule that specifically binds lysine, he immediately wanted to see if it could unglue amyloids. "I thought this could be the magic bullet I've been looking for," he says.
The lysine grabber is called CLR01 and is a molecular tweezer, a class of Pac-Man-shaped molecules designed to engulf a particular target. CLR01 binds to lysine somewhat weakly, about 1,000 times weaker than most drugs bind their targets, Bitan says. "They bite and hold onto lysine for a fraction of a second and then let go," he adds, but that's a good thing because if they bound too tightly they might interfere with the work of healthy proteins.
To test the tweezer's effects on amyloids, Bitan and his team first looked at amyloid-β, the protein associated with Alzheimer's disease. They mixed CLR01 with the protein and monitored the formation of amyloids using a dye that fluoresces upon binding to a common structural motif in amyloids. The fluorescence data revealed that CLR01 completely shuts down amyloid formation in solution.
The next question was whether the tweezer could save cells from amyloid-β aggregates. Normally, cultured cells die when mixed with these clumps. The researchers first primed the proteins to aggregate by mixing them in an aggregate-promoting solution and then they added the proteins to the cells either with or without the molecular tweezer. At a concentration that was about 100-times lower than a toxic one, the lysine grabber completely prevented cell death from the aggregates.
Amyloid-β is just one of several proteins that aggregate into noxious clumps; each amyloid disease has its own signature protein. So Bitan tested CLR01 against a total of nine amyloid-forming proteins, using a combination of the fluorescence and cell death tests, as well as others. Of the nine proteins, CLR01 inhibited the harmful aggregation of all but one, a prion, the protein responsible for diseases such as Creutzfeldt–Jakob disease. Bitan says this protein is an unusual case, because they tested only a fragment of a prion, as the full length protein is too dangerous to study in his laboratory.
James Shorter of the University of Pennsylvania calls the study "an important proof of principle experiment." He was surprised by the ability of CLR01 to wreak havoc on so many different types of amyloids "I think the broad specificity is really the interesting part of the study," he says.
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