p23 and Aha1 - The Networking of Chaperones by Co-chaperones - page 124

ND

C

CR

A P

MD

i

N

+Aha1

CD

open

C

N

C

closed 2

A

N

C

N

closed 1

Fig. 6.4 Integration of Aha1 and p23 into the Hsp90 cycle. Aha1 binds to the open conformation
of Hsp90 and accelerates dimerization of the N-terminal domains of Hsp90, leading to the closed 1
state. p23 is able to displace Aha1 from Hsp90 during the rearrangements leading to the closed 2
state. p23 inhibits the ATP turnover thereby decelerating the cycle. After ATP hydrolysis, ADP, Pi
and p23 dissociate from Hsp90, thereby enabling another cycle of ATP turnover. This model shall
not imply that both cochaperones have to be present in one ATPase cycle, but if they do, some
conformational changes will be accelerated while others will be decelerated

Consistent with p23's selective binding to the nucleotide-bound conformation of
Hsp90, p23 was able to fully replace Aha1 from Hsp90 in the presence of the ATP
analogues ATPγS and AMP-PNP (Harst et al. 2005 ; Li et al. 2013 ), while only a par-
tial release of Aha1 was observed in the presence of ATP (Li et al. 2013 ). Whether
the formation of a mixed ternary complex of Hsp90, Aha1 and p23 is possible is
controversial as the previous in vitro and in vivo results have come to different con-
clusions (Harst et al. 2005 ; Sun et al. 2012 ; Li et al. 2013 ).
The current knowledge allows the integration of p23 and Aha1 in the Hsp90
cycle (see Fig. 6.4 ). First, the N-domain of Aha1 binds to the open conformation of
Hsp90 thereby promoting N-terminal dimerization of Hsp90 leading to the closed 1
conformation. The dimerized N-domains of Hsp90 provide the binding site for the
C-terminal domain of Aha1. By conformational rearrangements of the middle do-
mains, closed 1 progresses to the closed 2 state, which is the p23-competent binding
state of Hsp90. During this progression, p23 competes with Aha1 for the Hsp90
binding site, resulting in a p23-bound state. p23 dissociates upon ATP hydrolysis
and Hsp90 can undergo another round of cycling (Li et al. 2013 ).