p23 and Aha1 - The Networking of Chaperones by Co-chaperones - page 121

+
+

H. sapiens

Aha2

N C

M. musculus

Aha2

N C

+

S. cerevisiae

N C Hch1

+
+

P. falciparum

N N C

T. gondii

N N C

E. histolytica

C

G. lamblia

N

a

C

C

C

N N N

b open closed 1 closed 2

Fig. 6.3 Evolutionary development of Aha1 and its binding to Hsp90. a Aha1 homologues from
higher and lower eukaryotes are schematically displayed to visualize the origin and evolution of
the Aha1 domains. The figure is modified from Singh et al. ( 2014 ). b Aha1 is able to bind in the
presence or absence of ATP. The N-domain of Aha1 interacts with the M-domain of Hsp90. Upon
dimerization of Hsp90, the C-domain of Aha1 is able to bind to the N-domains of Hsp90

Hsp90, the N-terminal domain of Aha1 interacts with the middle domain of Hsp90,
while the C-terminal domain of Aha1 contacts the N-domains of Hsp90 (Meyer
et al. 2004 ; Retzlaff et al. 2010 ; Koulov et al. 2010 ). In our current model, the
Aha1 N-domain serves as the primary binding site which is then followed by a bind-
ing of the C-terminal domain of Aha1 to the N-domains of Hsp90 once they dimer-
ize (Retzlaff et al. 2010 ). Consequently, Aha1 is able to interact with Hsp90 inde-
pendent of its nucleotide state (see Fig. 6.3b ), even though higher binding affinities
were observed for the nucleotide-bound state (Li et al. 2013 ). It had been recently
reported that N-domain SUMOylation of Hsp90 is able to initiate the recruitment of
Aha1 to Hsp90 (Mollapour et al. 2014 ). Many of the observed interactions between
Aha1 and Hsp90 are of polar nature, thus explaining the salt-dependence of this
complex (Panaretou et al. 2002 ; Meyer et al. 2004 ).
Via binding to Hsp90, Aha1 and Hch1 activate the ATPase activity of Hsp90
even though Hch1 and the isolated N-domain of Aha1 do so to a significant lower