Hsp70/Hsp90 Organising Protein (Hop): Beyond Interactions with Chaperones and Prion Proteins - The Networking of Chaperones by Co-chaperones - page 76

that Hsp70/Hsp90, or indeed PrP C , may fulfil as yet undefined roles in these seem-
ingly alternative functions of Hop.
Most recently, evidence has emerged to suggest that Hop has independent
ATPase activity (Yamamoto et al. 2014 ). Hop bound ATP with a similar affinity to
Hsp90 and Hsp70 but hydrolysis of ATP took place at a slower rate than in the two
chaperones. The ATPase activity of Hop was associated with the N terminal regions
of the protein, encompassing the TPR1, DP1 and TPR2A domains. While the DP1
domain was essential for ATPase activity, the mutation of a putative Walker B motif
in this domain did not abolish the ATPase activity of Hop (Yamamoto et al. 2014 ).
The consequences of this ATPase activity for the function of Hop remain to be de-
termined. However, ATP binding by Hop induced a conformational change in the
protein. The domains which display ATPase activity are those involved in binding
both Hsp70 (TPR1) and Hsp90 (TPR2A) and therefore it is plausible that the ATP
induced conformational changes may be involved in the transfer of client protein
between Hsp70 and Hsp90.
Hop as a Co-chaperone for Hsp70 and Hsp90
Hsp90 substrates include a diverse set of proteins, many of which have been im-
plicated in regulation of apoptosis (Samali and Cotter 1996 ; Mosser and Morimoto
2004 ; Lanneau et al. 2008 ), proliferation (Caplan et al. 2007 ; DeZwaan and Free-
man 2008 ; Lanneau et al. 2008 ), autophagy (Agarraberes and Dice 2001 ; Qing et al.
2006 ; Joo et al. 2011 ; Xu et al. 2011 ) and cell cycle progression (Francis et al.
2006 ; Reikvam et al. 2009 ) as well as in tumorigenesis (Kamal et al. 2004 ; Mller
et al. 2004 ; Whitesell and Lindquist 2005 ; Chiosis 2006 ; Neckers 2007 ; Mahalin-
gam et al. 2009 ; Trepel et al. 2010 ; Miyata et al. 2013 ). In early studies it was found
that Hsp90 interacted with the yeast and vertebrate homologues of Hop in lysates
of these cells (Chang et al. 1997 ). Deletion of the gene encoding Hop reduced the
in vivo activity of the Hsp90 target proteins, glucocorticoid receptor (GR) and the
oncogenic tyrosine kinase, v-Src (Chang et al. 1997 ). Hop was also shown to stimu-
late the refolding of luciferase by Hsp70 and a much more dramatic effect was seen
when Hsp90 was also included (Johnson et al. 1998 ). This led to the conclusion
that Hop is a general factor in the maturation of Hsp90 target proteins. Since then
it has been clearly demonstrated that Hop regulates the molecular chaperone ac-
tivities of Hsp70 and Hsp90 and thus plays a crucial role in the productive folding
of client proteins (Johnson et al. 1998 ; Kimmins and MacRae 2000 ; Wegele et al.
2004 ; Song and Masison 2005 ; Wegele et al. 2006 ; Kubota et al. 2010 ; Lee et al.
2012 ). These client proteins include a variety of kinases, transcription factors and
steroid hormone receptors, many of which are deregulated in cancer (Pratt and Toft
2003 ; Lee et al. 2004 ; Song and Masison 2005 ; Tan et al. 2011 ; Walsh et al. 2011 ;
Ruckova et al. 2012 ; Willmer et al. 2013 ). The central role of Hop in these processes
is demonstrated by mutations in Hop that impair the client folding pathway (Song
and Masison 2005 ). Hop connects Hsp90 and Hsp70 in a ternary multichaperone