Biology Reference
In-Depth Information
In vivo
, the effect of a molecular chaperone can be counterbalanced
by another chaperone. In addition, it is difficult to determine, with
accuracy, the concentration of the different molecular chaperones
and their variation throughout the cell cycle. Finally, not only is the
activity of molecular chaperones modulated by cofactors for which
concentration and activity vary over time, but their “specific activity”,
that is, the fraction of molecular chaperone A, B, or C that is available
to interact with prions, is also impossible to determine. Given that it
is very difficult to assess the exact role of each molecular chaperone
in prion propagation from
studies
were carried out to document the exact role of each molecular
chaperone in yeast prion assembly. Such studies are limited by the
variety of molecular chaperones to document, on the one hand, by
the number of molecular chaperone combinations one can make, on
the other.
Hsp104p was shown to reduce the nucleation phase preceding
assembly and strongly stimulate the apparent assembly rate of
full-length Sup35p. This effect could either be accounted for by an
Hsp104p-mediated remodelling of the fibrillar form of Sup35p, for
example, by fragmentation, with the generation of large number of
nuclei, or by an Hsp104p-mediated nucleation activity. One study
reported the active and GTP-mediated fragmentation of Sup35p by
Hsp104p,
in vivo
studies, a number
in vitro
97
while another reported no such activity, but instead that
Hsp104p favours
de novo
Sup35p oligomerization and nucleation.
98
Despite the lack of agreement of the Hsp104p mechanistic action,
both studies strongly suggest that the greater segregation efficiency
of the infectious Sup35p high molecular weight oligomers between
mother and daughter cells is the consequence of an Hsp104p-
mediated generation of Sup35p polymers that are smaller than those
that form in the absence or upon inactivation of Hsp104p.
Similar to what has been described for Sup35p, Hsp104p has
been reported to sever preformed Ure2p fibrils,
97
99
In
addition, while Sup35p assemblies are of fibrillar nature in the
presence of Hsp104p, Ure2p high molecular weight aggregates are
not.
or not.
98,99
They appear amorphous in the electron microscope, and
unlike Ure2p fibrils are SDS-sensitive.
99
Hsp70 family members
alone or in cooperation with their co-chaperones from the Hsp40
family sequester Sup35p and Ure2p in an assembly incompetent
state.
Finally, members of the Hsp40 family interact with Sup35p
and Ure2p and disfavour assembly into fibrils.
98,99
98,99
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