The Role of HSP70 and Its Co-chaperones in Protein Misfolding, Aggregation and Disease - The Networking of Chaperones by Co-chaperones - page 244

The potential mechanisms by which the HSP70 chaperone machine is neuro-
protective are manifold and complex. It seems likely that the HSP70 chaperone
machine prevents the conversion of native protein species into toxic intermediates
and either facilitates their degradation or, instead, pushes them towards a folding
pathway where non-toxic disordered aggregates form. The prominent role played
by HSP70 in the removal of toxic protein species by the UPS means that it helps
prevent unwanted interactions between misfolded proteins and important cellular
proteins such as transcription factors (Schaffar et al. 2004 ).
The HSP70 Chaperone Machine
The HSP70 chaperone machine is a key component of the cellular protein produc-
tion and quality control machinery. The frequent association of HSP70 proteins with
inclusions of misfolded disease protein suggests this chaperone machine is particu-
larly important in dealing with toxic misfolding disease proteins. HSP70 proteins
bind short regions of peptides with a certain position and pattern of hydrophobic
residues in a substrate-binding pocket, assisting in their stabilisation and folding
(Bukau and Horwich 1998 ; Hartl and Hayer-Hartl 2002 ). Substrate binding is cyclic
with HSP70 switching from a low substrate affinity, fast substrate exchange state
when bound to ATP to a high substrate affinity, slow substrate exchange state upon
the hydrolysis of ATP to ADP. HSP70 undergoes a conformational change resulting
in closure of its substrate binding pocket upon ATP hydrolysis (Bukau and Horwich
1998 ; Hartl and Hayer-Hartl 2002 ), dependent on interdomain communication via
an allosteric mechanism (Jiang et al. 2005 ). This cycle is regulated by HSP70 co-
chaperones and in particular HSP40 proteins, which are characterised by a highly
conserved 70-amino acid domain called the J-domain (Cheetham and Caplan 1998 ).
The J-domain interacts with HSP70 protein, stimulating ATP hydrolysis and alter-
ing substrate binding.
Currently, up to 13 HSP70 and 4 HSP70-related HSP110 (HSPH) genes have
been identified in humans coding for different members of the HSP70 family, in-
cluding the cytosolic constitutive heat shock 70 cognate, HSC70 (HSPA8), several
stress inducible forms of HSP70 and the endoplasmic reticulum resident glucose-
regulated protein 78, GRP78 or BiP (HSPA5). Many more HSP40 proteins have
been identified. As well as stimulating HSP70 ATPase activity, HSP40 proteins
can bind client proteins independently, directly facilitating targeting to HSP70
(Cheetham and Caplan 1998 ). Thus HSP40 proteins may provide a mechanism for
recruiting the HSP70 machine to its many cellular roles. Interestingly, some type
II HSP40 proteins, such as HSJ1 (DNAJB2) and MRJ (DNAJB6), are expressed at
higher levels in the brain than other tissues suggesting a specificity and/or particu-
lar requirements for HSP70 function in neurons (Chuang et al. 2002 ; Chapple and
Cheetham 2003 ).