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fibrillar assemblies that dictate the prion strain, other data suggest
that the establishment of intermolecular interactions between short
sequences within the region 1-121, residues 9-30, 59-86, and
90-130
govern the assembly of Sup35p into structurally distinct
high molecular weight protein oligomers at the origin of prion
strains variation.
In the case of Ure2p, real-time fluorescence microscopy observ-
ations have revealed that the fibrils are polar structures.
80
81
This
somehow suggests that the fibrillar scaffold is complex and that Ure2p
molecules are not stacked simply in-register in a cross-β structure.
Indeed, if the molecules were stacked as in a cross-β structure, the
two ends of the fibrils would be identical and the fibrils would not
exhibit polarity. In addition, a number of biochemical indications on
the molecular packing within the fibrils are available. Degradation
studies strongly suggest that both the N- and C-terminal domains
of the protein are involved in the fibrillar scaffold.63
63
Furthermore,
cross-linking studies indicate that the N- and C-terminal domains
of Ure2p are associated through intramolecular interactions within
monomeric Ure2p,
82
and have led to the identification of one of the
surface interfaces involved in intermolecular interactions within the
fibrils.
83
6.7
Molecular Chaperones and the Propagation
of Yeast Prions
Prion phenotypes can disappear spontaneously in yeast with a low
frequency (~10
−6
) comparable to chromosomal gene mutations.
84
The frequency with which a prion phenotype is lost upon cell division
defines the stability of a prion “strain” or “variant”. When yeast
prion “strains” were first observed, a difference in their propagation
efficiency upon overexpression of Hsp104 was described.
20,85
The
molecular chaperone Hsp104 is strictly required for yeast prion
propagation as strains carrying
HSP104
gene deletion are unable
+
85,86
to propagate the [PSI
Hsp104 is
not the only cellular factor necessary for the continued propagation
of prions in yeast cells. Other molecular chaperones play critical
roles.
] and the [URE3] phenotypes.
Indeed, the expression levels of Hsp70 family members have
been reported to be important for [PSI
87
+
] and [URE3] stability,
88-90
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