Navigation Links
Unweaving amyloid fibers to solve prion puzzles

Amyloid fibers are best known as the plaque that gunks up neurons in people with neurodegenerative illnesses such as Alzheimer's and Creutzfeldt-Jacob disease--the human analog of mad cow disease. But even though amyloids are common and implicated in a host of conditions, researchers haven't been able to identify their precise molecular structures. Conventional techniques used to image proteins, such as X-ray crystallography and nuclear magnetic resonance imaging, don't work with fibrous structures such as amyloids. And scientists depend on these high resolution images of molecules in order to study their function.

Now, researchers have found a way to work around these limitations, illuminating the configuration of these sometimes pernicious molecules. And even though this work was done in yeast, the results provide hints as to why mad-cow type diseases tend to have a difficult time jumping species.

"These findings give us some fundamental insights in how amyloid fibers form," says Whitehead Member Susan Lindquist, lead scientist in the research team whose results will be published in the June 9 issue of the journal Nature. "They solve the important problem of identifying the intermolecular contacts that hold the amyloid fiber together."

Amyloid fibers are often composed of prions--proteins that misfold and recruit neighboring proteins to misfold as well, a process that Lindquist calls a "conformational cascade." When such a cascade occurs, the prions join and form amyloid fibers. (While not all amyloids are composed of prions, all known prions, in their transmissible states, form amyloid fibers.) But still, many scientists have been frustrated by their inability to gain anything more than a limited understanding of an amyloid's architecture.

Rajaraman Krishnan, a postdoctoral researcher in Lindquist's lab, found a way around that problem using strains of yeast. Rather than develop a single high-tech method for solving the amyloid stru cture, he instead used a combination of low resolution tools to analyze varieties of prion strains and piece together the puzzle of how amyloids form.

"We now have an overall picture of how prions join together to form the amyloid's molecular structure," says Lindquist, who also is a professor of biology at MIT.

Prions are in the business of converting other prion molecules to join their ranks. And as they join together, they can create an amyloid fiber. To understand the nature of this fiber, it's necessary to understand how the prions that comprise it attach to each other. Krishnan was able to identify the precise segment at which the prions interact--something that no one had done before him with a real prion.

To do this, Krishnan took a variety of yeast prion strains and modified them in such a way that if particular designated regions came into contact with each other, they would emit a fluorescent signal, allowing him to map the pattern by which the different strains of prions interacted with each other.

He found that each prion molecule had only two points at which they connected to other prion molecules. One point he called the "head," the other the "tail." The head of one prion would only interact with the head of another prion, and likewise with tails. Remarkably, the same prion from the same yeast species could sometimes fold differently, and this fold would form its own cascade of interactions. In this altered form, the prion molecules interact in slightly different places, presenting different surfaces to promote the conversion of other prion molecules.

Lindquist believes that the techniques used in this study will ultimately prove useful for studying prion strains found in mammals like mice, cows, and ultimately humans.

"This gives us insight as to why some prions can't cross the species barrier while others can--as they have with mad cows and humans.," says Lindquist. That gap has also been observed betw een other species, she notes: "In fact, some type of prions from infected hamsters can't make the species jump into mice, while others do, and vice versa."

While the results of this research are clearly of interest to scientists investigating conditions such as Alzheimer's, it's also relevant to scientists studying nanotechnology. In March of 2003, Lindquist published a paper in the journal Proceedings of the National Academy of Sciences in which she described how amyloid fibers can become the core of nanoscale electrical wires, opening the possibility of one day incorporating them into integrated circuits.

"These findings are quite relevant for the material sciences," says Lindquist. "The more we understand about how these fibers work, the more we can get them to self-assemble," a key advantage for nanoscale devices that are very difficult to manipulate directly. In addition, amyloids are also unusually robust, which also makes them attractive for nano devices. The advantage of the yeast protein is that it is not toxic, even for yeast.


Source:Whitehead Institute for Biomedical Research

Related biology news :

1. Cerebral navigation: How do nerve fibers know what direction to grow in?
2. Virginia Tech scientists develop process for creating biocompatible fibers
3. Formation of cellulose fibers tracked for the first time
4. Biodegradable napkin -- featuring sensitive nanofibers -- may quickly detect biohazards
5. Lungs try to repair damaged elastic fibers
6. Tiny particles could solve billion-dollar problem
7. Scientists solve structure of key protein in innate immune response
8. Could microbes solve Russias chemical weapons conundrum?
9. Brown-Harvard team solves mobile DNAs surgical sleight-of-hand
10. Scripps research scientists solve structure of a critical innate immune system protein
11. Sperm trading can resolve hermaphrodite mating conflicts
Post Your Comments:

(Date:11/17/2015)... -- Vigilant Solutions announces today that Mr. Dick W. ... --> --> Mr. Boyce ... at TPG Capital, one of the largest global investment ... revenue.  He founded and led TPG,s Operating Group, which ... 1997 to 2013.  In his first role, he served ...
(Date:11/12/2015)...  Arxspan has entered into an agreement with ... use of its ArxLab cloud-based suite of biological ... will support the institute,s efforts to electronically manage ... internally and with external collaborators. The ArxLab suite ... Institute,s electronic laboratory notebook, compound and assay registration, ...
(Date:11/10/2015)... YORK , Nov. 10, 2015 ... to behavioral biometrics that helps to identify and ... fraud. Signature is considered as the secure and ... the identification of a particular individual because each ... more accurate results especially when dynamic signature of ...
Breaking Biology News(10 mins):
(Date:11/25/2015)... 25, 2015 The Global ... a professional and in-depth study on the current ... (Logo: ) , The ... including definitions, classifications, applications and industry chain structure. ... international markets including development trends, competitive landscape analysis, ...
(Date:11/24/2015)... N.J. (PRWEB) , ... November 24, 2015 , ... The ... the recipient of the 2016 USGA Green Section Award. Presented annually since 1961, the ... through his or her work with turfgrass. , Clarke, of Iselin, N.J., ...
(Date:11/24/2015)... VANCOUVER , Nov. 24, 2015 /CNW/ - iCo ... ICOTF), today reported financial results for the quarter ... are expressed in Canadian dollars and presented under ... the United States ," said Andrew ... "These advancements regarding iCo-008 are not only value ...
(Date:11/24/2015)... - Aeterna Zentaris Inc. (NASDAQ:  AEZS) (TSX: AEZ) (the "Company"), ... Toronto Stock Exchange, confirms that as of the date ... that would cause the recent movements in the Company,s ... About Aeterna Zentaris Inc. . ... Zentaris is a specialty biopharmaceutical company engaged in developing ...
Breaking Biology Technology: