Suramin is a novel activator of PP5 and biphasically modulates S100-activated PP5 activity.
Suramin is an activator of ryanodine receptors and competitively binds to the calmodulin-binding site. In addition, S100A1 and calmodulin compete for the same binding site on ryanodine receptors. We therefore studied the effects of suramin on protein phosphatase 5 (PP5) and S100-activated PP5. In the absence of S100 proteins, suramin bound to the tetratricopeptide repeat (TPR) domain of PP5 and activated the enzyme in a dose-dependent manner. In the presence of S100A2/Ca(2+), lower concentrations of suramin dose-dependently inhibited PP5 activity as an S100 antagonist, whereas higher concentrations of suramin reactivated PP5. Although the C-terminal fragment of heat shock protein 90 (HspC90) also weakly activated PP5, the binding site of suramin and HspC90 may be different, and addition of suramin showed no clear effect on the phosphatase activity of PP5. Similar biphasic effects of suramin were observed with S100A1-, S100B- or S100P-activated PP5. However, the inhibitory effects of lower concentrations of suramin on S100A6-activated PP5 are weak and high concentrations of suramin further activated PP5. SPR and the cross-linking study showed inhibition of the interaction between S100 protein and PP5 by suramin. Our results revealed that suramin is a novel PP5 activator and modulates S100-activated PP5 activity by competitively binding to the TPR domain.
Department of Cell Physiology, Faculty of Medicine, Kagawa University, 1750-1, Ikenobe, Miki-cho, Kita-gun, Kagawa, 761-0793, Japan.
Fuminori
F
Yamaguchi
Sho
S
Yamamura
Seiko
S
Shimamoto
Hiroshi
H
Tokumitsu
Masaaki
M
Tokuda
Ryoji
R
Kobayashi
D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D009687:Nuclear Proteins / Q000737:chemistry / Q000378:metabolism*; D010749:Phosphoprotein Phosphatases / Q000737:chemistry / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D009418:S100 Proteins / Q000378:metabolism*; D013498:Suramin / Q000378:metabolism / Q000494:pharmacology*
D018841:HSP90 Heat-Shock Proteins; D009687:Nuclear Proteins; D009418:S100 Proteins; D013498:Suramin; D010749:Phosphoprotein Phosphatases; C089641:protein phosphatase 5