Dynamic tyrosine phosphorylation modulates cycling of the HSP90-P50(CDC37)-AHA1 chaperone machine.
Many critical protein kinases rely on the Hsp90 chaperone machinery for stability and function. After initially forming a ternary complex with kinase client and the cochaperone p50(Cdc37), Hsp90 proceeds through a cycle of conformational changes facilitated by ATP binding and hydrolysis. Progression through the chaperone cycle requires release of p50(Cdc37) and recruitment of the ATPase activating cochaperone AHA1, but the molecular regulation of this complex process at the cellular level is poorly understood. We demonstrate that a series of tyrosine phosphorylation events, involving both p50(Cdc37) and Hsp90, are minimally sufficient to provide directionality to the chaperone cycle. p50(Cdc37) phosphorylation on Y4 and Y298 disrupts client-p50(Cdc37) association, while Hsp90 phosphorylation on Y197 dissociates p50(Cdc37) from Hsp90. Hsp90 phosphorylation on Y313 promotes recruitment of AHA1, which stimulates Hsp90 ATPase activity, furthering the chaperoning process. Finally, at completion of the chaperone cycle, Hsp90 Y627 phosphorylation induces dissociation of the client and remaining cochaperones.
Urologic Oncology Branch, National Cancer Institute, Bethesda, MD 20892, USA.
Wanping
W
Xu
Mehdi
M
Mollapour
Chrisostomos
C
Prodromou
Suiquan
S
Wang
Bradley T
BT
Scroggins
Zach
Z
Palchick
Kristin
K
Beebe
Marco
M
Siderius
Min-Jung
MJ
Lee
Anthony
A
Couvillon
Jane B
JB
Trepel
Yoshihiko
Y
Miyata
Robert
R
Matts
Len
L
Neckers
D000818:Animals; D019556:COS Cells; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D018833:Chaperonins / Q000235:genetics / Q000378:metabolism*; D002522:Chlorocebus aethiops; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D051379:Mice; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism*; D041681:NIH 3T3 Cells; D010766:Phosphorylation / Q000502:physiology; D014443:Tyrosine / Q000378:metabolism*
C515652:AHSA1 protein, human; C575823:Ahsa1 protein, mouse; C498362:CDC37 protein, human; C513271:Cdc37 protein, mouse; D018797:Cell Cycle Proteins; D018841:HSP90 Heat-Shock Proteins; D018832:Molecular Chaperones; D014443:Tyrosine; D018833:Chaperonins