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Abstract:
he ATPase-driven dimeric molecular Hsp90 (heat shock
protein90)anditscofactorCdc37(celldivisioncycle37protein)
are crucial to prevent the cellular depletion of many protein
kinases. In complex with Hsp90, Cdc37 is thought to bind an
important lid structure in the ATPase domain of Hsp90 and
inhibit ATP turnover by Hsp90. As different interaction modes
havebeenreported,wewereinterestedintheinteractionmech-
anism of Hsp90 and Cdc37. We find that Cdc37 can bind to one
subunitoftheHsp90dimer.TheinhibitionoftheATPaseactiv-
ity is caused by a reduction in the closing rate of Hsp90 without
obviously bridging the two subunits or affecting nucleotide
accessibility to the binding site.
Although human Cdc37 binds to
the N-terminal domain of Hsp90, nematodal Cdc37 preferentially
interacts with the middle domain of CeHsp90 and hHsp90, expos-
ing two Cdc37 interaction sites. A previously unreported site in
CeCdc37 is utilized for the middle domain interaction. Dephos-
phorylation of CeCdc37 by the Hsp90-associated phosphatase
PPH-5, a step required during the kinase activation process, pro-
ceeds normally, even if only the new interaction site is used. This
shows that the second interaction site is also functionally relevant
and highlights that Cdc37, similar to the Hsp90 cofactors Sti1 and
Aha1,mayutilizetwodifferentattachmentsitestorestrictthecon-
formational freedom and the ATP turnover of Hsp90