March 08, 2001
“Promiscuous Prion” Yields Clues to Infection Across Species Barriers
By stitching together segments of two species of infectious yeast
proteins, called prions, researchers have produced a hybrid prion that
can adopt two distinct infectious shapes. This ability to change
conformation allows the hybrid prion to bridge a species barrier and
"infect" proteins from two distantly related species of yeast. This
phenomenon, say the scientists, may be a key to understanding how
prions derived from cows infected with bovine spongiform encephalopathy
(BSE), or "mad cow disease," can hop the species barrier and infect
humans.
The ability of a single prion protein to fold into multiple
infectious forms, say the scientists, means that knowledge of the shape
of a prion, and not simply what species it came from, is critical to
understanding which hosts it can infect. The researchers also speculate
that the shape of a prion may evolve as it passes from host to host. If
this is the case, then the processing of animal parts for subsequent
use as feed for other animals may actually have selected for animal
prions with conformations that are especially virulent, says Jonathan
S. Weissman, a Howard Hughes Medical Institute investigator at the
University of California, San Francisco (UCSF).
“It might have been this very process that humans set up that made the bovine prion so virulent and created the epidemic of mad cow disease.”
Jonathan S. Weissman
Weissman and graduate student Peter Chien of UCSF published their
studies in the March 8, 2001, issue of the journal Nature.
The scientists conducted their studies using yeast prions, which are
similar to the mammalian prions that have gained notoriety for their
roles in such fatal brain-destroying human diseases such as
Creutzfeldt-Jakob disease and kuru, and in the animal diseases BSE and
scrapie.
Both yeast and mammalian prions are proteins that transmit their
characteristics via protein-protein interactions in which an abnormally
shaped prion protein influences its normal counterpart to assume an
abnormal shape. In mammalian prion infections, abnormal, insoluble
shapes trigger protein clumping that can kill brain cells. In yeast
cells, the insoluble prion protein is not deadly; it merely alters a
cell's metabolism. "In mammalian prions, it was known that the same
prion protein, even within genetically identical hosts, could cause
more than one type of disease," said Weissman. "And similarly, the same
yeast prions could have different strains with different
characteristics.
"This strain diversity had been one of the greatest mysteries about
prions," he said. "Although it had been proposed that prion strain
differences resulted from alternative conformations of the prion
protein itself, the theory was difficult to test directly. The problem
was that in mammalian prions it was never possible to unambiguously
create the infectious form of the prion with the pure protein in
vitro. So it couldn’t be ruled out that there were other
components that caused the apparent differences in conformation."
Chien and Weissman chose to use yeast prions because the pure
proteins are easily manipulated and propagated in vitro. Their
work built on earlier studies from the Weissman lab that demonstrated
that a species barrier prevented cross infection between prions derived
from two distantly related yeast species, Saccharomyces
cerevisae (SC) or Candida albicans (CA).
In the present studies, the scientists produced a chimera of the SC
and CA prion proteins by combining one segment of the SC prion with
another segment of the CA prion.
"We found that this chimera was ‘promiscuous,’" said
Weissman. "That is, it could be converted to the aggregated prion form
by either species of yeast, thus bridging the species barrier. However,
the prion strain conformation that resulted in each case was
dramatically different.
"But the really remarkable thing was that each of these alternate
conformations could subsequently induce conversion of only the yeast
species that had initially seeded it, but not the other," said
Weissman. "It was surprising that we would get such a clean and simple
answer—that this phenomenon that had been so mysterious and
difficult to study could be shown with a pure protein to be due
directly to self-propagating differences in conformation."
According to Weissman, discovery of the conformational basis of
different yeast prion strains has important implications for
understanding mammalian prions.
"We cannot take comfort in the fact that the cow prion protein has a
different sequence than the human prion, because if the cow prion has
assumed a conformation that’s virulent in humans, it won’t
be held up effectively by a species barrier," he said.
"An important lesson both from the mammalian prion work and from our
studies is that there is no simple answer to the question of whether we
are protected from being infected by prions from animals such as cows,"
said Weissman. "The key factor will be a prion's strain conformation,
which means that it will be critically important to understand on a
molecular level the differences among mammalian prion strains." Also,
he said, the effects of treatment of prion-containing meat might have
enhanced the virulence of the prions.
"While this remains speculative, it could be that the prion strain
changed as it was passaged," he said. "There might have been a kind of
evolution based on selection of a strain conformation among a diversity
of conformations, rather than mutations in a DNA genome as occurs with
viruses or cellular life.
"What we are learning from both yeast and mammalian prions raises
the disturbing possibility that the process of infecting,
heat-rendering of the animal parts, and then re-infecting cows might
actually have selected for a prion strain conformation that is
particularly virulent and resistant to being inactivated," Weissman
said. "So, it might have been this very process that humans set up that
made the bovine prion so virulent and created the epidemic of mad cow
disease."
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