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the role of molecular chaperones in the stability of prion phenotypes,
and the aggregation of yeast prions, have shown that molecular
chaperones bind and remodel prion high molecular weight
oligomeric forms. They have also shown that the levels of molecular
chaperones tune, in a very tight manner, the aggregation of prions,
and certainly the emergence of the prion phenotypes. It is therefore
reasonable to envisage that the reintroduction of a high molecular
weight oligomeric forms of a prion within a cell imbalances the
molecular chaperone proteostasis allowing the
formation
of an infectious form. One could argue that this cannot account for
the strain-specific phenotypes and indeed, one could easily imagine
that fibrils and soluble high molecular weight oligomers possessing
different quaternary structures; in other words, those that expose
a different surface area to the solvent, interact with different
molecular chaperones. As a consequence, the functional pool of
chaperones can vary in cells where aggregates of different types have
been introduced, and “strain-specific” prion high molecular weight
aggregates can form and propagate
de novo
. Thus, the emergence
and propagation of a particular yeast prion strain could be the
combined consequence of a specific change in the functional pool of
molecular chaperones, on the one hand, and a nucleated assembly
process, on the other. Yeast prions do not spread from cell to cell.
They are stably inherited by daughter cells from mothers or passed
between partners during mating. To better assess the potential role
of molecular chaperones in the
de novo
formation of prion particles
and the propagation of prion phenotypes it is critical to (i) document
the changes in molecular chaperone functional pool and expression
profile upon introduction of recombinant fibrillar prion within cells,
(ii) determine whether the molecular chaperone-binding pattern
of different types of fibrillar prions differ, and how, by a proteomic
approach.
The assembly of yeast prions is often considered as being driven
by polyQ/N extensions. This is certainly not the case for HET-s as
the latter protein lacks Q and N residues in its PrD(s). In addition,
the increase of Q and N proportion in the N-terminal domain of
Ure2p from 46% (in wild-type Ure2p) to 54% (in a variant Ure2p)
is accompanied by a marked reduction in assembly.
de novo
This clearly
indicates that assembly is not solely driven by the Q/N extensions of
yeast prions.
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