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Papers - YAMAMOTO Sou

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Geranylgeranylacetone selectively binds to the HSP70 of Helicobacter pylori and alters its coccoid morphology.

Ewa Grave, Shin-ichi Yokota, Soh Yamamoto, Arisa Tamura, Takako Ohtaki-Mizoguchi, Kenji Yokota, Keiji Oguma, Kazuhiko Fujiwara, Nobuaki Ogawa, Tomoya Okamoto, Michiro Otaka, Hideaki Itoh

Scientific reports ( NATURE PUBLISHING GROUP ) 5 13738 - 13738 2015.09 [Refereed] [International journal]

Geranylgeranylacetone (GGA) is used to treat patients suffering from peptic ulcers and gastritis. We examined the effect of GGA on Helicobacter pylori, which is a causative factor of gastrointestinal diseases. Previously, we have reported that GGA binds specifically to the molecular chaperone HSP70. In this paper, we report that GGA bounds to H. pylori HSP70 (product of the DnaK gene) with 26-times higher affinity than to human HSP70, and induced large conformational changes as observed from surface plasmon resonance and circular dichroism. Binding of GGA suppressed the activity of the H. pylori chaperone. GGA also altered several characteristics of H. pylori cells. GGA-treated cells elicited enhanced interleukin-8 production by gastric cancer cell lines and potentiated susceptibility to complement as compared to untreated cells. GGA also caused morphological alterations in H. pylori as reflected in fewer coccoid-like cells, suggesting that GGA converts H. pylori to an actively dividing, spiral state (vegetative form) from a non-growing, coccoid state. This morphological conversion by GGA resulted in accelerated growth of H. pylori. These results suggest a model in which GGA sensitizes H. pylori to antibiotic treatment by converting the cells to an actively growing state.

DOI PubMed

Structural characterization of the substrate transfer mechanism in Hsp70/Hsp90 folding machinery mediated by Hop

Sara Alvira, Jorge Cuellar, Alina Roehl, Soh Yamamoto, Hideaki Itoh, Carlos Alfonso, German Rivas, Johannes Buchner, Jose M. Valpuesta

NATURE COMMUNICATIONS ( NATURE PUBLISHING GROUP ) 5 5484 2014.11 [Refereed]

In eukarya, chaperones Hsp70 and Hsp90 act coordinately in the folding and maturation of a range of key proteins with the help of several co-chaperones, especially Hop. Although biochemical data define the Hop-mediated Hsp70-Hsp90 substrate transfer mechanism, the intrinsic flexibility of these proteins and the dynamic nature of their complexes have limited the structural studies of this mechanism. Here we generate several complexes in the Hsp70/Hsp90 folding pathway (Hsp90: Hop, Hsp90: Hop: Hsp70 and Hsp90: Hop: Hsp70 with a fragment of the client protein glucocorticoid receptor (GR-LBD)), and determine their 3D structure using electron microscopy techniques. Our results show that one Hop molecule binds to one side of the Hsp90 dimer in both extended and compact conformations, through Hop domain rearrangement that take place when Hsp70 or Hsp70: GR-LBD bind to Hsp90: Hop. The compact conformation of the Hsp90: Hop: Hsp70: GR-LBD complex shows that GR-LBD binds to the side of the Hsp90 dimer opposite the Hop attachment site.

DOI PubMed

ATPase Activity and ATP-dependent Conformational Change in the Co-chaperone HSP70/HSP90-organizing Protein ( HOP)*

Soh Yamamoto, Ganesh Prasad Subedi, Shinya Hanashima, Tadashi Satoh, Michiro Otaka, Hideki Wakui, Ken-ichi Sawada, Shin-ichi Yokota, Yoshiki Yamaguchi, Hiroshi Kubota, Hideaki Itoh

JOURNAL OF BIOLOGICAL CHEMISTRY ( AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC ) 289 ( 14 ) 9880 - 9886 2014.04 [Refereed]

Authorship： Lead author

Background: HOP assists protein transfer in the HSP70- and HSP90-dependent protein-folding pathway. Results: HOP hydrolyzed ATP, and the region containing amino acids 1-359 (TPR1-TPR2A) was required for hydrolysis and direct interaction with ATP. Conclusion: HOP has slow ATPase activity and changes its conformation upon ATP hydrolysis. Significance: This is the first demonstration of the ATPase activity of HOP, and may enhance our understanding of the physiological function. Co-chaperones help to maintain cellular homeostasis by modulating the activities of molecular chaperones involved in protein quality control. The HSP70/HSP90-organizing protein (HOP) is a co-chaperone that cooperates with HSP70 and HSP90 in catalysis of protein folding and maturation in the cytosol. We show here that HOP has ATP-binding activity comparable to that of HSP70/HSP90, and that HOP slowly hydrolyzes ATP. Analysis of deletion mutants revealed that the ATPase domain of HOP is in the N-terminal TPR1-DP1-TPR2A segment. In addition, HOP changes its conformation in the presence of ATP. These results indicate that HOP is a unique co-chaperone that undergoes an ATP-dependent conformational change.

DOI PubMed

The activation mechanism of the aryl hydrocarbon receptor (AhR) by molecular chaperone HSP90

Noriko Tsuji, Kana Fukuda, Yuhtaroh Nagata, Hirotaka Okada, Asami Haga, Shiori Hatakeyama, Shiho Yoshida, Tomoya Okamoto, Miki Hosaka, Kazuhiro Sekine, Kei Ohtaka, Soh Yamamoto, Michiro Otaka, Ewa Grave, Hideaki Itoh

FEBS OPEN BIO ( ELSEVIER SCIENCE LONDON ) 4 796 - 803 2014 [Refereed]

The aryl hydrocarbon receptor is a member of the nuclear receptor superfamily that associates with the molecular chaperone HSP90 in the cytoplasm. The activation mechanism of the AhR is not yet fully understood. It has been proposed that after binding of ligands such as 2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD), 3methylcholanthrene (3-MC), or beta-naphthoflavone (beta-NF), the AhR dissociates from HSP90 and translocates to the nucleus. It has also been hypothesized that the AhR translocates to the nucleus and forms a complex with HSP90 and other co-chaperones. There are a few reports about the direct association or dissociation of AhR and HSP90 due to difficulties in purifying AhR. We constructed and purified the PAS domain from AhR. Binding of the AhR-PAS domain to beta-NF affinity resin suggested that it possesses ligand-binding affinity. We demonstrated that the AhR-PAS domain binds to HSP90 and the association is not affected by ligand binding. The ligand 17-DMAG inhibited binding of HSP90 to GST-PAS. In an immunoprecipitation assay, HSP90 was co-immunoprecipitated with AhR both in the presence or absence of ligand. Endogenous AhR decreased in the cytoplasm and increased in the nucleus of HeLa cells 15 min after treatment with ligand. These results suggested that the ligand-bound AhR is translocated to nucleus while in complex with HSP90. We used an in situ proximity ligation assay to confirm whether AhR was translocated to the nucleus alone or together with HSP90. HSP90 was co-localized with AhR after the nuclear translocation. It has been suggested that the ligand-bound AhR was translocated to the nucleus with HSP90. Activated AhR acts as a transcription factor, as shown by the transcription induction of the gene CYP1A1 8 h after treatment with beta-NF. (C) 2014 The Authors. Published by Elsevier B.V. on behalf of the Federation of European Biochemical Societies.

DOI PubMed

Aminoglycosides Suppress the Protein Folding Activity of the Molecular Chaperone HSC70: Implication of a Structure-Activity Relationship

Soh Yamamoto, Hideki Wakui, Hiroshi Kubota, Atsushi Kornatsuda, Hideaki Itoh, Shin-Ichi Yokota

CHEMOTHERAPY ( KARGER ) 60 ( 1 ) 37 - 46 2014 [Refereed]

Authorship： Lead author

Background: The mechanism of aminoglycoside (AG)-induced nephrotoxicity has not been fully elucidated. We previously reported that gentamicin suppresses the functions of HSC70, a heat shock cognate protein, which is a cytosolic molecular chaperone in mammalian cells. However, the relationship between HSC70 dysfunction and nephrotoxicity has not been clarified yet. Methods: The effects of 11 AGs, including gentamicin, on the function, protein refolding and substrate binding of HSC70 were examined in vitro. The protein refolding activity of HSC70 was examined by enzymatic activity restoration of the denatured firefly luciferase. Substrate binding activity of HSC70 was examined by the binding of fluorescent-dye-labeled reduced carboxymethlylated alpha-lactalbumin determined by HSC70/substrate complex formation by native polyacrylamide gel electrophoresis. Results: Strong inhibitory activity of AGs on the protein refolding activity of HSC70 was observed for arbekacin, gentamicin, neomycin and sisomicin, but not spectinomycin, streptomycin, ribostamycin and paromomycin, and inhibition was weak for tobramycin, amikacin and kanamycin. Neomycin strongly suppressed the formation of the HSC70/substrate complex and had the lowest concentration that resulted in 50% inhibition (IC50; in the order of 10(-4) nn). Arbekacin, gentamicin, sisomicin and tobramycin had IC50 values in the order of 10(-3) M. Amikacin, ribostamycin and paromomycin had no effective potencies. Conclusions: The inhibition efficacies of AGs for protein refolding of HSC70 were as follows: neomycin >> gentamicin, arbekacin, and sisomicin > tobramycin, amikacin and kanamycin > spectinomycin, streptomycin, ribostamycin and paromomycin. Amino groups and/or hydroxyl groups located at 2', 3',4', and 6' of amino sugar residue II, as well as the number of amino sugar rings were closely associated with the inhibition efficacies of AGs. Inhibition efficacies of AGs towards the function of HSC70 correlated well with the nephrotoxicity of AGs deduced from the in vivo studies previously reported. Amino groups/hydroxyl groups and the number of amino sugar rings of AGs were shown to be important for inhibition efficacies. The results strongly suggest that the AG-induced dysfunction of HSC70 is involved in the nephrotoxicity. (C) 2014 S. Karger AG, Basel

DOI PubMed

Positive Relationship Between a Polymorphism in Helicobacter pylori Neutrophil-Activating Protein A Gene and Iron-Deficiency Anemia

Shin-ichi Yokota, Nariaki Toita, Soh Yamamoto, Nobuhiro Fujii, Mutsuko Konno

HELICOBACTER ( WILEY-BLACKWELL ) 18 ( 2 ) 112 - 116 2013.04 [Refereed]

Background Numerous studies have suggested a link between iron-deficiency anemia (IDA) and Helicobacter pylori infection. Previously, we found that strains isolated from IDA patients showed higher levels of Fe ion uptake and Fe-ion-dependent rapid proliferation than those of strains derived from patients without IDA. Materials and Methods Twenty-four H.pylori strains from IDA patients (IDA strains) and 25 strains from patients who had H.pylori gastritis without anemia (non-IDA strains) were examined. Their nucleotide sequences of napA, fur, and feoB, which contribute to Fe ion uptake, were determined. Results Numerous polymorphisms of the three genes were found in both strains. Frequency of neutrophil-activating protein A (NapA), which encoded by napA, with threonine at amino acid residue No. 70 (Thr70-type NapA) was significantly higher in IDA strains than in non-IDA strains. Strains with Thr70-type NapA showed significantly higher levels of Fe3+ and Fe2+ uptake than did strains with other types, Ser70-type of NapA, which is found in standard strains. Other significantly different occurrences of polymorphisms between IDA and non-IDA groups were not observed in these genes. Conclusion The results suggest that H.pylori strains with Thr70-type NapA have enhanced Fe ion uptake ability and are associated with the pathogenesis of IDA.

DOI PubMed

Imiquimod Suppresses Propagation of Herpes Simplex Virus 1 by Upregulation of Cystatin A via the Adenosine Receptor A(1) Pathway

Yuji Kan, Tamaki Okabayashi, Shin-ichi Yokota, Soh Yamamoto, Nobuhiro Fujii, Toshiharu Yamashita

JOURNAL OF VIROLOGY ( AMER SOC MICROBIOLOGY ) 86 ( 19 ) 10338 - 10346 2012.10 [Refereed]

Imiquimod is recognized as an agonist for Toll-like receptor 7 (TLR7) in immunocompetent cells. TLR7, as well as TLR3 and TLR8, triggers the immune responses, such as the production of type I interferons (IFNs) and proinflammatory cytokines via recognition of viral nucleic acids in the infected cells. In this study, we proposed that imiquimod has an IFN-independent antiviral effect in nonimmune cells. Imiquimod, but not resiquimod, suppressed replication of human herpes simplex virus 1 (HSV-1) in FL cells. We analyzed alternation of gene expression by treatment with imiquimod using microarray analysis. Neither type I IFNs, nor TLRs, nor IFN-inducible antiviral genes were induced in imiquimod-treated FL cells. Cystatin A, a host cysteine protease inhibitor, was strongly upregulated by imiquimod and took a major part in the anti-HSV-1 activity deduced by the suppression experiment using its small interfering RNA. Upregulation of cystatin A was suggested to be mediated by antagonizing adenosine receptor A(1) and activating the protein kinase A pathway. Imiquimod, but not resiquimod, was shown to interact with adenosine receptor A(1). Imiquimod-induced anti-HSV-1 activity was observed in other cells, such as HeLa, SiHa, and CaSki cells, in a manner consistent with the cystatin A induction by imiquimod. These results indicated that imiquimod acted as an antagonist for adenosine receptor A(1) and induced a host antiviral protein, cystatin A. The process occurred independently of TLR7 and type I IFNs.

DOI PubMed

Cytosolic chaperonin CCT possesses GTPase activity

Susumu Noguchi, Kazuyoshi Toyoshima, Soh Yamamoto, Toshio Miyazaki, Michiro Otaka, Sumio Watanabe, Katsunori Imai, Haruki Senoo, Ryoji Kobayashi, Mitsutoshi Jikei, Yasushi Kawata, Hiroshi Kubota, Hideaki Itoh

Am. J. Mol. Biol. 1 ( 3 ) 383 - 390 2012 [Refereed]

Traditional Herbal Medicine, Rikkunshito, Induces HSP60 and Enhances Cytoprotection of Small Intestinal Mucosal Cells as a Nontoxic Chaperone Inducer

Kumiko Tamaki, Michiro Otaka, Tomoyoshi Shibuya, Naoto Sakamoto, Soh Yamamoto, Masaru Odashima, Hideaki Itoh, Sumio Watanabe

EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE ( HINDAWI PUBLISHING CORPORATION ) 2012 1 - 7 2012 [Refereed]

Increasing incidence of small intestinal ulcers associated with nonsteroidal anti-inflammatory drugs (NSAIDs) has become a topic with recent advances of endoscopic technology. However, the pathogenesis and therapy are not fully understood. The aim of this study is to examine the effect of Rikkunshito (TJ-43), a traditional herbal medicine, on expression of HSP60 and cytoprotective ability in small intestinal cell line (IEC-6). Effect of TJ-43 on HSP60 expression in IEC-6 cells was evaluated by immunoblot analysis. The effect of TJ-43 on cytoprotective abilities of IEC-6 cells against hydrogen peroxide or indomethacin was studied by MTT assay, LDH-release assay, caspase-8 activity, and TUNEL. HSP60 was significantly induced by TJ-43. Cell necrosis and apoptosis were significantly suppressed in IEC-6 cells pretreated by TJ-43 with overexpression of HSP60. Our results suggested that HSP60 induced by TJ-43 might play an important role in protecting small intestinal epithelial cells from apoptosis and necrosis in vitro.

DOI PubMed

Evidence for Enhanced Cytoprotective Function of HSP90-Overexpressing Small Intestinal Epithelial Cells

Kumiko Tamaki, Michiro Otaka, Makiko Takada, Soh Yamamoto, Masaru Odashima, Hideaki Itoh, Sumio Watanabe

DIGESTIVE DISEASES AND SCIENCES ( SPRINGER ) 56 ( 7 ) 1954 - 1961 2011.07 [Refereed]

In the clinical field, increasing incidence of small intestinal ulcers associated with nonsteroidal anti-inflammatory drugs (NSAIDs) has become a topic with the advances of capsule endoscopy and balloon enteroscopy technology for the detection of small intestinal lesions. However, the pathogenesis of NSAID-induced mucosal damage, defensive mechanism of intestinal epithelial cells, and therapy for small intestinal mucosal lesion have not been fully understood. Heat shock proteins (HSPs) are involved in cytoprotection mediated by their function as a molecular chaperone. Since the function of HSP90 in the intestinal epithelial cells has not been well investigated, we examined the cytoprotective ability of HSP90-overexpressing small intestinal epithelial cells against hydrogen peroxide-induced or indomethacin-induced cell damage. cDNA of human HSP90 gene was transfected to rat small intestinal epithelial cells (IEC-6 cells), and HSP90-overexpressing cells (IEC-6-90 cells) were selected and cloned. Anti-necrotic abilities and anti-apoptotic abilities of IEC-6-90 cells were compared with IEC-6-mock cells (transfected with vector alone). To examine the specific contribution of HSP90 on cytoprotection of IEC-6-90 cells, cytoprotective ability of IEC-6-90 cells was analyzed with or without pretreatment with functional inhibitor of HSP90, geldanamycine analog, followed by hydrogen peroxide-challenge or indomethacin-challenge. Hydrogen peroxide-induced or indomethacin-induced cell necrosis and apoptosis were significantly suppressed in IEC-6-90 cells. The cytoprotective ability of IEC-6-90 cells was suppressed by HSP90 inhibitor. Our results suggest that HSP90 might play an important role in protecting small intestinal epithelial cells from hydrogen peroxide-induced or indomethacin-induced cell injury in vitro, and raised the possibility of protection of small intestinal epithelial cells by manipulation of HSP90 expression.

DOI PubMed

Increased expression of co-chaperone HOP with HSP90 and HSC70 and complex formation in human colonic carcinoma

Hiroshi Kubota, Soh Yamamoto, Eri Itoh, Yuki Abe, Asami Nakamura, Yukina Izumi, Hirotaka Okada, Masatake Iida, Hiroshi Nanjo, Hideaki Itoh, Yuzo Yamamoto

CELL STRESS & CHAPERONES ( SPRINGER ) 15 ( 6 ) 1003 - 1011 2010.11 [Refereed]

Co-chaperone HOP (also called stress-inducible protein 1) is a co-chaperone that interacts with the cytosolic 70-kDa heat shock protein (HSP70) and 90-kDa heat shock protein (HSP90) families using different tetratricopeptide repeat domains. HOP plays crucial roles in the productive folding of substrate proteins by controlling the chaperone activities of HSP70 and HSP90. Here, we examined the levels of HOP, HSC70 (cognate of HSP70, also called HSP73), and HSP90 in the tumor tissues from colon cancer patients, in comparison with the non-tumor tissues from the same patients. Expression level of HOP was significantly increased in the tumor tissues (68% of patients, n = 19). Levels of HSC70 and HSP90 were also increased in the tumor tissues (95% and 74% of patients, respectively), and the HOP level was highly correlated with those of HSP90 (r = 0.77, p < 0.001) and HSC70 (r = 0.68, p < 0.01). Immunoprecipitation experiments indicated that HOP complexes with HSC70 or HSP90 in the tumor tissues. These data are consistent with increased formation of co-chaperone complexes in colon tumor specimens compared to adjacent normal tissue and could reflect a role for HOP in this process.

DOI PubMed

Overexpression of a 60-kDa heat shock protein enhances cytoprotective function of small intestinal epithelial cells

Makiko Takada, Michiro Otaka, Taiji Takahashi, Yuko Izumi, Kumiko Tamaki, Tomoyoshi Shibuya, Naoto Sakamoto, Taro Osada, Sou Yamamoto, Ryuichi Ishida, Masaru Odashima, Hideaki Itoh, Sumio Watanabe

LIFE SCIENCES ( PERGAMON-ELSEVIER SCIENCE LTD ) 86 ( 13-14 ) 499 - 504 2010.03 [Refereed]

Aims With the advancement of small intestinal (double balloon and capsule) endoscopy technology, incidence of small intestinal lesion caused by nonsteroidal anti-inflammatory drugs (NSAIDs) has been known to be high However, therapy for small intestinal mucosal lesion has not yet been developed Previous studies have shown that heat shock proteins (HSPs) are involved in cytoprotection mediated by their function as a molecular chaperone In this study, we examined the effect of HSP60 or HSP70 overexpression on hydrogen peroxide-induced (H(2)O(2)) or indomethacin-induced cell damage in the small intestinal epithelial cells Main methods cDNA of human HSP60 or HSP70 was transfected to rat small intestinal (IEC-6) cells, and HSP60- or HSP70-overexpressing cells were cloned IEC-6 cells transfected with vector only were used as control cells These cells were treated with H(2)O(2) (0-0 14 mM) or indomethacin (0-25 mM) The cell viability was determined by MIT-assay. Cell necrosis was evaluated by LDH-release assay Furthei, apoptosis was evaluated by caspases-3/7 activity and TUNEL assay Key findings Cell viability after H(2)O(2) or indomethacin treatment was significantly higher in HSP60-overexpiessing cells compared with that in control cells and HSP60-overexpressing cells Apoptotic cells were also reduced in HSP60-overexpressing Conclusion These results indicate that HSP60 plays an important role in protecting small intestinal mucosal cells from H(2)O(2)-induced or indomethacin-induced cell injury HSP70-overexpressing cells did not show anti-apoptotic ability Significance These findings possibly suggest that function of each HSP is different in the small intestine Therefore, for the therapy of small intestinal mucosal lesion. HSP60-induction therapy could be a new therapeutic strategy (C) 2010 Elsevier Inc All rights reserved.

DOI PubMed

Gentamicin inhibits HSP70-assisted protein folding by interfering with substrate recognition

Soh Yamamoto, Shunsuke Nakano, Kensuke Owari, Kazuhiko Fuziwara, Nobuaki Ogawa, Michiro Otaka, Kumiko Tamaki, Sumio Watanabe, Atsushi Komatsuda, Hideki Wakui, Ken-ichi Sawada, Hiroshi Kubota, Hideaki Itoh

FEBS LETTERS ( ELSEVIER SCIENCE BV ) 584 ( 4 ) 645 - 651 2010.02 [Refereed]

Authorship： Lead author

We previously reported that gentamicin (GM) specifically binds to heat-shock protein with subunit molecular masses of 70 kDa (HSP70). In the present study, we have investigated the effects of GM binding on HSP70-assisted protein folding in vitro. The C-terminal, and not the N-terminal of HSP70 was found to bind to GM. GM significantly suppressed refolding of firefly luciferase in the presence of HSP70 and HSP40, although the ATPase activity of HSP70 was unaffected by GM. A surface plasmon resonance analysis revealed that GM specifically interferes with the binding of HSP70 to a model peptide that mimics the exposed hydrophobic surface of the folding intermediates. These results indicated that GM inhibits the chaperone activity of HSP70 and may suppress protein folding via inhibition of HSP70 in vivo.

DOI PubMed

Angiotensin Receptor Blocker Directly Binds to HSP and Stimulates its Production in the Brain

Taku Sugawara, Kohei Kokubun, Ryuichi Ishida, Kazuhiko Fujiwara, Sou Yamamoto, Hiroyuki Kinouchi, Hideaki Itoh, Kazuo Mizoi

RECENT ADVANCES IN MATHEMATICS AND COMPUTERS IN BUSINESS, ECONOMICS, BIOLOGY & CHEMISTRY ( WORLD SCIENTIFIC AND ENGINEERING ACAD AND SOC ) 350 - + 2010 [Refereed]

Antihypertensive angiotensin II type 1 receptor blockers (ARBs) have neuroprotective effects that were independent of the reduction of blood pressure. We have previously shown that vulnerable hippocampal CA1 neurons underwent delayed cell death through mitochondria-dependent apoptotic pathway after global cerebral ischemia, but ARB protected these neurons from cell death. To elucidate the mechanism of neuroprotection by ARB candesartan, candesartan-specific binding proteins were first investigated using candesartan-affinity column and rat hippocampal tissue. And, the affinity of ARB and the binding protein was further examined by BIAcore binding assay. Then, the distribution and expression of the protein were characterized by immunohisotochemistry and Western blots. By affinity column study, molecular chaperone heat shock protein 90 (HSP90) was identified as a binding target of candesartan. BIAcore assay proved functional binding of candesartan to HSP90. Immunohistochemistry showed increased HSP90 expression in the hippocampal CA1 neurons as early as 1 day after candesartan treatment. Westen blots confirmed temporal changes in HSP90 expression.HSP90 maintains the stability of the proteins as a molecular chaperone and has been recently proven to inhibit apoptosis in in vitro studies. Our data suggest that HSP90 may play an important role in neuronal protection by ARB treatment through blocking mitochondria-dependent apoptosis.

Cisplatin differently affects amino terminal and carboxyl terminal domains of HSP90

Ryuichi Ishida, Yuka Takaoka, Soh Yamamoto, Toshio Miyazaki, Michiro Otaka, Sumio Watanabe, Atushi Komatsuda, Hideki Wakui, Ken-ichi Sawada, Hiroshi Kubota, Hideaki Itoh

FEBS LETTERS ( ELSEVIER SCIENCE BV ) 582 ( 28 ) 3879 - 3883 2008.11 [Refereed]

The 90-kDa heat shock protein (HSP90) is a molecular chaperone that assists in the folding and assembly of proteins in the cytosol. We previously demonstrated that the antineoplastic reagent, cisplatin, inhibits the aggregation prevention activity of mammalian HSP90. We now show that cisplatin binds both the amino terminal and carboxyl terminal domains of the human HSP90 and differently affects these two domains. Cisplatin blocks the aggregation prevention activity of HSP90C, but not HSP90N. In contrast, cisplatin induces a conformational change in HSP90N, but not HSP90C. These results indicate that cisplatin modulates the HSP90 activities through two different mechanisms using the two distinct binding sites of the HSP90 molecule. (C) 2008 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

DOI PubMed

The induction mechanism of the molecular chaperone HSP70 in the gastric mucosa by Geranylgeranylacetone (HSP-inducer)

Michiro Otaka, Soh Yamamoto, Kaori Ogasawara, Yuka Takaoka, Susumu Noguchi, Toshio Miyazaki, Akira Nakai, Masaru Odashima, Tamotsu Matsuhashi, Sumio Watanabe, Hideaki Itoh

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS ( ACADEMIC PRESS INC ELSEVIER SCIENCE ) 353 ( 2 ) 399 - 404 2007.02 [Refereed]

To elucidate the induction mechanism of HSP70 by geranylgeranylacetone (GGA), we investigated GGA specific binding proteins using a GGA-affinity column. Alteration of chaperone activity of HSP70 and binding affinity of HSP70 to heat shock factor-1 (HSF1) was evaluated in the presence or absence of GGA. The binding domain of HSP70 to GGA was also analyzed. A 70-kDa protein eluted by 10 mM GGA from the GGA-affinity column was identical to constitutively expressed HSP70 on immunoblotting. GGA-binding domain of HSP70 was C-terminal of the protein as peptide-binding domain (HSP70C). The chaperone activity of HSP70 and recombinant HSP70C was suppressed by GGA. Furthermore, dissociation of the HSP70 from HSF-I was observed in the presence of GGA. GGA preferentially binds to the C-terminal of HSP70 which binds to HSF-1. After dissociation of HSP70, free HSF-1 could acquire the ability to bind to HSE (the promoter region of HSP70) gene. (c) 2006 Elsevier Inc. All rights reserved.

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Papers - YAMAMOTO Sou