Unweaving amyloid fibers to solve
prion puzzles
CAMBRIDGE, Mass. (June 8, 2005) — 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.
"These findings give us some fundamental
insights in how amyloid fibers form. They solve
the important problem of identifying the intermolecular
contacts that hold the amyloid fiber together."
Whitehead Member
Susan Lindquist |
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.
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 between 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.
This research was partially funded by DuPont.
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