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The functional interplay between Hsp104p and the Hsp70-40
systems and the consequences of changes in the cellular levels of
molecular chaperones on the assembly of Sup35p and Ure2p into
high molecular weight oligomers, in particular fibrils, were also
documented
by varying the concentrations of molecular
chaperones in Sup35p and Ure2p assembly reactions and measuring
the affinity of molecular chaperones for the prion proteins. Hsp70/40
possess higher affinities for Sup35p and Ure2p than Hsp104p, and
were also shown to counteract the assembly stimulatory effect of
Hsp104p.
in vitro
98,99
The differences in affinities of the Hsp70/40 system
and Hsp104p for yeast prions, and their sequestering and assembly
promoting activities, suggest that molecular chaperones expression
levels in a dividing yeast cell and variations in these levels throughout
the cell cycle, or when the cells are subject to stress, finely tune the
propagation and cure of the [PSI
+
] and [
URE3
] prion traits (Fig. 6.5).
6.8
Nature of the Infectious Form of
Yeast Prions
The fibrillar form of Sup35p, Ure2p, Rnq1p, and HET-s is widely
believed to be the infectious form of these prion proteins, responsible
for the emergence and propagation of the prion phenotypes [PSI
+
],
[PIN
], [URE3], and [Het-s]. Indeed, an ultra-structural analysis
suggested that Ure2p might be fibrillar in [URE3] cells.
+
100
In addition,
fibrils made
in vitro
from recombinant Sup35p, Ure2p, Rnq1p, and
HET-s induce the
appearance of the prion phenotypes when
re-introduced in yeast or cells of filamentous fungi.
de novo
101-105
However,
it is important to bear in mind that the fibrillar form of prions are in
equilibrium with soluble oligomeric forms that are introduced within
the cells at the same time as the fibrillar form. It is therefore unclear
whether the fibrillar form is the only infectious form and the specific
infectivity of the different oligomeric forms remains unknown.
Nucleated assembly is the simplest molecular process that can
account for the propagation of a prion phenotype upon introduction
within a cell of a mixture of fibrillar and oligomeric non-fibrillar
forms of the recombinant prion. However, one can envisage that
prion phenotype emergence and propagation upon introduction
within a cell of oligomeric forms of a recombinant prion is the
consequence of other events. Indeed,
in vivo
and
in vitro
studies of
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