Asymmetric Hsp90 N domain SUMOylation recruits Aha1 and ATP-competitive inhibitors.
The stability and activity of numerous signaling proteins in both normal and cancer cells depends on the dimeric molecular chaperone heat shock protein 90 (Hsp90). Hsp90's function is coupled to ATP binding and hydrolysis and requires a series of conformational changes that are regulated by cochaperones and numerous posttranslational modifications (PTMs). SUMOylation is one of the least-understood Hsp90 PTMs. Here, we show that asymmetric SUMOylation of a conserved lysine residue in the N domain of both yeast (K178) and human (K191) Hsp90 facilitates both recruitment of the adenosine triphosphatase (ATPase)-activating cochaperone Aha1 and, unexpectedly, the binding of Hsp90 inhibitors, suggesting that these drugs associate preferentially with Hsp90 proteins that are actively engaged in the chaperone cycle. Importantly, cellular transformation is accompanied by elevated steady-state N domain SUMOylation, and increased Hsp90 SUMOylation sensitizes yeast and mammalian cells to Hsp90 inhibitors, providing a mechanism to explain the sensitivity of cancer cells to these drugs.
Department of Urology, SUNY Upstate Medical University, 750 East Adams Street, Syracuse, NY 13210, USA; Department of Biochemistry and Molecular Biology, SUNY Upstate Medical University, 750 East Adams Street, Syracuse, NY 13210, USA; Cancer Research Institute, SUNY Upstate Medical University, 750 East Adams Street, Syracuse, NY 13210, USA; Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, 9000 Rockville Pike, Bethesda, MD 20892, USA. Electronic address: mollapom@upstate.edu.
Mehdi
M
Mollapour
Department of Urology, SUNY Upstate Medical University, 750 East Adams Street, Syracuse, NY 13210, USA; Department of Biochemistry and Molecular Biology, SUNY Upstate Medical University, 750 East Adams Street, Syracuse, NY 13210, USA; Cancer Research Institute, SUNY Upstate Medical University, 750 East Adams Street, Syracuse, NY 13210, USA; Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, 9000 Rockville Pike, Bethesda, MD 20892, USA.
Dimitra
D
Bourboulia
Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, 9000 Rockville Pike, Bethesda, MD 20892, USA.
Kristin
K
Beebe
Department of Urology, SUNY Upstate Medical University, 750 East Adams Street, Syracuse, NY 13210, USA.
Mark R
MR
Woodford
Genome Damage and Stability Centre, University of Sussex, Brighton BN1 9RQ, UK.
Sigrun
S
Polier
Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, 9000 Rockville Pike, Bethesda, MD 20892, USA.
Anthony
A
Hoang
Department of Urology, SUNY Upstate Medical University, 750 East Adams Street, Syracuse, NY 13210, USA.
Raju
R
Chelluri
Cell Signaling Technology, Danvers, MA 01923, USA.
Yu
Y
Li
Cell Signaling Technology, Danvers, MA 01923, USA.
Ailan
A
Guo
Medical Oncology Branch, Center for Cancer Research, National Cancer Institute, 9000 Rockville Pike, Bethesda, MD 20892, USA.
Min-Jung
MJ
Lee
Medical Oncology Branch, Center for Cancer Research, National Cancer Institute, 9000 Rockville Pike, Bethesda, MD 20892, USA.
Elham
E
Fotooh-Abadi
Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, 9000 Rockville Pike, Bethesda, MD 20892, USA.
Sahar
S
Khan
Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, 9000 Rockville Pike, Bethesda, MD 20892, USA.
Thomas
T
Prince
Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, 9000 Rockville Pike, Bethesda, MD 20892, USA.
Naoto
N
Miyajima
Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, 9000 Rockville Pike, Bethesda, MD 20892, USA.
Soichiro
S
Yoshida
Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, 9000 Rockville Pike, Bethesda, MD 20892, USA.
Shinji
S
Tsutsumi
Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, 9000 Rockville Pike, Bethesda, MD 20892, USA.
Wanping
W
Xu
Institute of Pharmaceutical Science, Kings College London, London SE1 9NH, UK.
Barry
B
Panaretou
Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, 9000 Rockville Pike, Bethesda, MD 20892, USA.
William G
WG
Stetler-Stevenson
Department of Urology, SUNY Upstate Medical University, 750 East Adams Street, Syracuse, NY 13210, USA; Cancer Research Institute, SUNY Upstate Medical University, 750 East Adams Street, Syracuse, NY 13210, USA.
Gennady
G
Bratslavsky
Medical Oncology Branch, Center for Cancer Research, National Cancer Institute, 9000 Rockville Pike, Bethesda, MD 20892, USA.
Jane B
JB
Trepel
Genome Damage and Stability Centre, University of Sussex, Brighton BN1 9RQ, UK.
Chrisostomos
C
Prodromou
Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, 9000 Rockville Pike, Bethesda, MD 20892, USA. Electronic address: neckers@nih.gov.
Len
L
Neckers
D000255:Adenosine Triphosphate / Q000378:metabolism*; D018833:Chaperonins / Q000378:metabolism*; D018841:HSP90 Heat-Shock Proteins / Q000737:chemistry / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D017434:Protein Structure, Tertiary; D012441:Saccharomyces cerevisiae / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism*; D058207:Sumoylation
C475092:AHA1 protein, S cerevisiae; D018841:HSP90 Heat-Shock Proteins; D029701:Saccharomyces cerevisiae Proteins; D000255:Adenosine Triphosphate; D018833:Chaperonins