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CAMBRIDGE, Mass. -- Small peptide segments -- typically only 19 amino acids in length -- govern the switch from a normal protein to a self-perpetuating infectious prion, according to researchers here.
CAMBRIDGE, Mass., May 9 -- Small peptide segments -- typically only 19 amino acids in length -- govern the switch from a normal protein to a self-perpetuating infectious prion, according to researchers here.
The same regions of the protein also govern whether the resulting prion can jump from one species to another, according to Susan Lindquist, Ph.D., of the Whitehead Institute for Biomedical Research.
The finding may shed new light on the development and transmission of prion-related disorders, such as bovine spongiform encephalopathy, the so-called mad-cow disease, Dr. Lindquist and Peter Tessier, Ph.D., reported online in Nature.
Bovine spongiform encephalopathy is a prion disease that affects cattle, but was apparently transmitted to humans in what is now called variant Creutzfeldt-Jakob disease. About one in a million people yearly is affected by the sporadic human form of Creutzfeldt-Jakob disease.
The prion protein involved in bovine spongiform encephalopathy and variant Creutzfeldt-Jakob disease was dubbed PrP, which, in its normal form, is found in healthy cells.
But when it switches shape to become PrpSc it causes other PrP proteins to follow suit and they go on to form clumps of amyloid, which destroy brain tissue, causing dementia and death.
The current findings "provide a new framework for us to begin exploring properties of prion biology that, up until now, have proven difficult to investigate," Dr. Lindquist said.
The researchers used peptide arrays, usually used to find the active binding sites of well-behaved proteins, to observe prion proteins misfolding and then creating self-perpetuating assemblies of prions.
Initially, they used a non-toxic prion protein derived from yeast and found that five regions of the protein - dubbed "recognition elements" -- both cause the change to a prion and begin a "conformational cascade" that converts other proteins of the same type to prions, Dr. Lindquist said.
Then, using a prion protein from Candida albicans - whose amino acid sequence is almost entirely unlike the yeast protein - they found a similar pattern: seven 19-amino acid regions that promoted the change to the prion form and began converting others.
Finally, they used a chimeric prion protein, created in the lab of another group that has been shown to cause prion conversion in both yeast and C. albicans.
That protein was able to bind to recognition elements from both species, offering a possible explanation of how the prion involved in bovine spongiform encephalopathy was able to leap from cattle to humans, the researchers said.
Interestingly, when the chimeric protein was tested at 25 degrees Celsius, it interacted with both species, but when it was tested at four degrees, it only interacted with yeast proteins and at 37 degrees only with C. albicans.
The finding implies that environmental conditions may play a role in whether prion proteins are able to be transmitted, the researchers said.