Biology Reference
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and mutations in both the peptide or the ATP-binding site of a
number of Hsp70 family members abolish [URE3] propagation.
91,92
Finally, [URE3] and [PIN
] faithful propagation is dependent on the
overexpression levels of members of the hsp40 family as [URE3] is
lost upon the overexpression of Ydj1p,
+
86,88
+
while [PIN
] propagation
93
A number of models have been proposed to account for the
role played by molecular chaperones in the maintenance or the
destabilization of the prion phenotypes. In one model, the elevated
levels of molecular chaperones facilitate the disaggregation and
remodelling of the high molecular weight species of prion proteins
that act as seeds.
requires the expression of Sis1p.
94,95
Such a remodelling activity may generate
sites for the incorporation of additional prion proteins and favour
prion protein aggregation. In another model, molecular chaperones
disfavour assembly by sequestering either the folding inter-
mediate(s) that assemble into prion aggregates, or the cellular
factor(s) that are required for the generation of the high molecular
weight species of prion proteins that act as seeds.
90
Molecular
chaperones have also been attributed with a mechanistic role in the
propagation from mother to daughter cells of Sup35p and Ure2p high
molecular weight aggregates associated with [PSI
96
Additional roles for molecular chaperones can be proposed.
Molecular chaperones could act on prion protein conformers
and modulate prion aggregation either by refolding or unfolding
conformers that are aggregation prone, or by facilitating prion folding
into aggregation prone states. In the first case, molecular chaper-
ones will have an unfavourable effect on oligomerization, while in
the second, they will favour the aggregation reaction. Molecular
chaperones could also act as a matrix, imprinting a structure to
prion oligomeric species, thus mimicking a seed and favouring
assembly. Similarly, assembly could be facilitated by the interaction
of several prion molecules with a single molecular chaperone
as the latter becomes a sort of local concentrator facilitating the
thermodynamically unfavourable nucleation process. Finally,
molecular chaperones could restrain prion aggregation either by
pacifying elongation sites, favouring the bundling of prion aggregates,
thus reducing the exposure to the solvent of elongation sites, or
sequester assembly competent prion conformers into structured or
amorphous aggregates (Fig. 6.5).
+
] and [URE3].
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