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 structure, 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.