Cdc37 as a Co-chaperone to Hsp90 - The Networking of Chaperones by Co-chaperones - page 105

hydrolysis, a reaction that leads to loss of affinity for the client protein (Fig. 5.1 ).
Cdc37 binding to Hsp90 appears to inhibit this latter ATPase activity of Hsp90 and
to permit prolonged interactions between chaperone and client (Fig. 5.1 )(Cox and
Johnson 2011 ). During the interaction with Hsp90, Cdc37 binds both to the client
kinase as well as to hsp90 itself and both interactions are required for chaperone
function (Gray et al. 2008 ). Cdc37 binds to the highly conserved N-loop of protein
kinases and is thought to stabilize the aC-b4 loop, while Hsp90 binds both the N
and C lobes (Discussed in more detail in Gray et al 2008 ). , Two distinct client in-
teraction domains have been described in mammalian Cdc37, including a conserved
N-terminal domain as well as a C terminal domain that is not conserved in yeast
Cdc37 (Calderwood 2013 ). Thus Cdc37 is a molecular chaperone itself that, at least
in Yeast appears to have independent protein interaction functions but that in mam-
malian cells more commonly operates in cooperation with Hsp90 to optimally fold
the structures of protein kinases (MacLean and Picard 2003 ; Turnbull et al. 2005 ).
Cdc37 has been shown to bind to the catalytic domains of a large number of client
kinases, structures that appear to be conserved in all protein kinases suggesting a
common mode of interaction with a range of such enzymes (Caplan et al. 2007a ;
Taipale et al. 2012 ; Vaughan et al. 2006 ). However, such Cdc37-kinase interactions
are by no means uniform in nature. For instance Hsp90-Cdc37 complexes are re-
quired to maintain Cdk4 in folded conformation only until such kinases encounter
the regulatory Cyclin D1 subunits when they then become chaperone-independent
rev. (Caplan et al. 2007a ). The oncogenic receptor tyrosine kinase ERBB2 by con-
trast requires persistent association with Hsp90-Cdc37 complexes for stability and
activity (Caplan et al. 2007a ). Indeed quantitative studies of Hsp90/Cdc37 complex/
kinase client interactions show that even closely related kinase family members
interact with quite different affinities. Another principle involved in Cdc37/client
interactions seems to be that the chaperone complex binds most avidly to the more
unstable protein kinases and stabilization of clients led to reduced association (Tai-
pale et al. 2012 ). In addition, it has been shown that the exchange of ATP in acti-
vated kinase clients during enzymatic activity leads to their increased instability
and enhanced chaperone binding (Gray et al. 2008 ). Interestingly, but in accordance
with the prior statements, it would appear that protein kinase catalytic activities may
be reduced under Cdc37/Hsp90 complex-bound conditions, as determined for the
LKB1 kinase (Taipale et al. 2012 ). Dissociation of LKB1 from the Cdc37/Hsp90
complex led to transient activation of kinase activity prior to degradation via a path-
way involving association with Hsp70 family proteins, recruitment of ubiquitin li-
gase CHIP and breakdown in the proteasome (Xu and Neckers 2012 ).
Posttranslational Modifications of Cdc37 and Hsp90
The Hsp90/Cdc37 interaction is also regulated by posttranscriptional modifications
(PTM) that affect profoundly the chaperoning cycle. Both proteins appear to be sub-
strates for casein kinase 2 (CK2), an enzyme that is in fact also a client (Miyata and