Chaperones, Molecular
Partially folded
Folded protein
Fig. 7
Holders, folders, and unfolders in a chaperone network. A folded
protein may become partially unfolded (for example, due to heat shock). It may
refold spontaneously from this state, or may require the assistance of a
‘‘folder’’ chaperone (F), such as the GroEL/ES or DnaK/J systems. The partially
unfolded state may interact further with other proteins in the same state to
form an aggregate. This can be reversed by the action of an ‘‘unfolder’’ (such
as ClpB). Alternatively, a ‘‘holder’’ chaperone (such as an sHSP) may hold the
intermediate in a nonactive but nonaggregated state until a folder chaperone
can refold it.
always an option, otherwise there would be
no need for the cellular proteases to exist.
Protein Quality Control in the
Endoplasmic Reticulum
The ER is of particular importance in the
quality control of protein folding. It is the
site for several important covalent modi-
Fcations that are key to protein structure,
including disulFde bond formation and
glycosylation, and proteins pass through
the ER en route to the plasma membrane
and beyond, where they will be inaccessible
to any further modiFcation by chaperones.
Thus, a substantial machinery is found
within the ER to ensure that proteins are
correctly folded and modiFed, and that
leads to the degradation of those that are
not. The components of this machinery
include proteins that form and isomerize
disulFde bonds, a key Hsp70 homolog, sev-
eral proteins with DnaJ domains, and two
proteins called calnexin and calreticulin.
Other proteins with chaperone activity also
exist in the ER (for example, an Hsp90
homolog called Grp94), although genetic
evidence suggests they play a relatively
minor role.
The Hsp70 protein homolog (also re-
ferred to as BiP, Grp78, and Kar2p) can
be shown to associate with incompletely
folded proteins using the same rules for
binding as other members of the Hsp70
family. BiP has a C-terminal amino acid
signal that retains it in the ER by cycles of
retrieval from the Golgi body, and so any
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