2022/11/07 更新

写真a

ヒビノ エミ
日比野 絵美
HIBINO Emi
所属
大学院創薬科学研究科 基盤創薬学専攻 創薬分子構造学 助教
大学院担当
大学院創薬科学研究科
職名
助教
連絡先
メールアドレス
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外部リンク

学位 1

  1. 博士 (薬科学) ( 2017年3月   京都大学 ) 

研究キーワード 6

  1. アミロイド

  2. 天然変性タンパク質

  3. タンパク質間相互作用

  4. アルツハイマー病

  5. p53

  6. NMR

研究分野 2

  1. ライフサイエンス / 生物物理学

  2. ライフサイエンス / 薬系分析、物理化学

現在の研究課題とSDGs 1

  1. がん抑制タンパク質p53に着目した新規抗がん薬の開発

経歴 4

  1. 名古屋大学   創薬科学研究科   助教

    2022年4月 - 現在

  2. 滋賀医科大学   神経難病研究センター   客員助教

    2020年6月 - 現在

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  3. 名古屋大学   創薬科学研究科   特任助教

    2020年6月 - 2022年3月

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  4. 滋賀医科大学   神経難病研究センター   特任助教

    2017年4月 - 2020年5月

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    国名:日本国

学歴 2

  1. 京都大学大学院   薬学研究科

    2011年4月 - 2017年3月

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  2. 京都大学   薬学部   薬科学科

    2007年4月 - 2011年3月

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所属学協会 5

  1. 日本生物物理学会

  2. 日本生化学会

  3. 日本蛋白質科学会

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  4. 日本核磁気共鳴学会

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  5. 日本薬学会

 

論文 17

  1. Moesin-ezrin-radixin-like protein merlin and its conserved and distinct functions from those of ERM proteins.

    Senju Y, Hibino E

    Biochimica et biophysica acta. Biomembranes     頁: 184076   2022年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1016/j.bbamem.2022.184076

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  2. Direct inhibition of the first PDZ domain of ZO-1 by glycyrrhizin is a possible mechanism of tight junction opening of Caco-2 cells.

    Hibino E, Goda N, Hisada M, Tenno T, Hiroaki H

    Food & function   13 巻 ( 4 ) 頁: 1953 - 1964   2022年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Food and Function  

    Glycyrrhizin (GL) is known to exhibit a variety of useful pharmacological activities, including anti-inflammation, anti-hepatotoxicity, and enhancement of intestinal drug absorption. GL has been reported to modify the assembly of actin filaments, thereby modulating tight junction (TJ) integrity, but the detailed molecular mechanisms of this remain unclear. In this study, we first found that GL binds to the first PDZ domain of zonula occludens-1 (ZO-1(PDZ1)) through NMR experiments. The structure of the GL-ZO-1(PDZ1) complex was then constructed using HADDOCK with the transferred nuclear Overhauser effect-based inter-hydrogen distance constraints as well as restrictions on the interfacial residues identified from 1H-15N HSQC spectral changes. We identified the relevant interactions between the glucuronate-2 moiety of GL and the carboxylate binding loop of the ligand binding site of ZO-1(PDZ1). We further examined the interaction of ZO-1(PDZ1) with glycyrrhetinic acid and with GA-3-monoglucuronide and observed a much lower affinity for each than for that with GL, with good agreement with the model. The other contacts found in the model were examined by using an amino acid substitution mutant of ZO-1(PDZ1). Finally, we reproduced the experiments reported by Sakai et al. in which high-dose GL prolonged the TJ-opening mediated with sodium deoxycholate as indicated by reduced transepithelial electrical resistance. This journal is

    DOI: 10.1039/d1fo03062k

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  3. Bex1 is essential for ciliogenesis and harbours biomolecular condensate-forming capacity.

    Hibino E, Ichiyama Y, Tsukamura A, Senju Y, Morimune T, Ohji M, Maruo Y, Nishimura M, Mori M

    BMC biology   20 巻 ( 1 ) 頁: 42   2022年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:BMC Biology  

    Background: Primary cilia are sensory organelles crucial for organ development. The pivotal structure of the primary cilia is a microtubule that is generated via tubulin polymerization reaction that occurs in the basal body. It remains to be elucidated how molecules with distinct physicochemical properties contribute to the formation of the primary cilia. Results: Here we show that brain expressed X-linked 1 (Bex1) plays an essential role in tubulin polymerization and primary cilia formation. The Bex1 protein shows the physicochemical property of being an intrinsically disordered protein (IDP). Bex1 shows cell density-dependent accumulation as a condensate either in nucleoli at a low cell density or at the apical cell surface at a high cell density. The apical Bex1 localizes to the basal body. Bex1 knockout mice present ciliopathy phenotypes and exhibit ciliary defects in the retina and striatum. Bex1 recombinant protein shows binding capacity to guanosine triphosphate (GTP) and forms the condensate that facilitates tubulin polymerization in the reconstituted system. Conclusions: Our data reveals that Bex1 plays an essential role for the primary cilia formation through providing the reaction field for the tubulin polymerization.

    DOI: 10.1186/s12915-022-01246-x

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  4. Potential of rescue and reactivation of tumor suppressor p53 for cancer therapy.

    Hibino E, Hiroaki H

    Biophysical reviews   14 巻 ( 1 ) 頁: 267 - 275   2022年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Biophysical Reviews  

    The tumor suppressor protein p53, a transcription product of the anti-oncogene TP53, is a critical factor in preventing cellular cancerization and killing cancer cells by inducing apoptosis. As a result, p53 is often referred to as the “guardian of the genome.” Almost half of cancers possess genetic mutations in the TP53 gene, and most of these mutations result in the malfunction of p53, which promotes aggregation. In some cases, the product of the TP53 mutant allele shows higher aggregation propensity; the mutant co-aggregates with the normal (functional) p53 protein, thus losing cellular activity of the p53 guardian. Cancer might also progress because of the proteolytic degradation of p53 by activated E3 ubiquitination enzymes, MDM2 and MDM4. The inhibition of the specific interaction between MDM2 (MDM4) and p53 also results in increased p53 activity in cancer cells. Although the molecular targets of the drugs are different, two drug discovery strategies with a common goal, “rescuing p53 protein,” have recently emerged. To conduct this approach, various biophysical methods of protein characterization were employed. In this review, we focus on these two independent strategies based on the unique biophysical features of the p53 protein.

    DOI: 10.1007/s12551-021-00915-5

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  5. A special issue of the Australian society for Biophysics.

    Dos Remedios C, Cranfield C, Whelan D, Cox C, Shearwin K, Ho J, Allen T, Shibuya R, Hibino E, Hayashi K, Li A

    Biophysical reviews   14 巻 ( 1 ) 頁: 1 - 2   2022年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Biophysical Reviews  

    On behalf of the Australian Society for Biophysics (ASB) and the Editors of this Special Issue, I would like to express our appreciation to Editor-in-Chief, Damien Hall, for arranging the publication of this Special Issue. The ASB is about five times smaller than our sister the Biophysical Society for Japan (BSJ) and tenfold smaller than the US Biophysical Society (USBS), but our meetings are notable because of the encouragement the Society gives to emerging biophysicists. It can be a terrifying experience for a PhD student to have to face a roomful of professors and senior academics, but invariably they appreciate the experience. Another feature of the ASB meetings is the inclusion of contributions from the Asian Pacific region. We now have formal ties with our New Zealand colleagues and our meetings with the BSJ contain joint sessions (see below). In 2020, despite the impact of COVID-19 (see Adam Hill’s Commentary), there is a joint session with the University of California Davis. This Special Issue comprises 2 Editorials, 3 Commentaries, and 25 reviews.

    DOI: 10.1007/s12551-022-00936-8

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  6. Relevance of Amorphous and Amyloid-Like Aggregates of the p53 Core Domain to Loss of its DNA-Binding Activity.

    Hibino E, Tenno T, Hiroaki H

    Frontiers in molecular biosciences   9 巻   頁: 869851   2022年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Frontiers in Molecular Biosciences  

    The anti-oncogenic protein p53 is a transcription factor that prevents tumorigenesis by inducing gene repair proteins or apoptosis under DNA damage. Since the DNA-binding domain of p53 (p53C) is aggregation-prone, the anti-oncogenic function of p53 is often lost in cancer cells. This tendency is rather severe in some tumor-related p53 mutants, such as R175H. In this study, we examined the effect of salts, including KCl and sugars, on the aggregation of p53C by monitoring two distinct aggregates: amorphous-like and amyloid-like. The amorphous aggregates are detectable with 8-(phenylamino)-1-naphthalenesulfonic acid (ANS) fluorescence, whereas the amyloid aggregates are sensitive to thioflavin-T (ThT) fluorescence. We found that KCl inhibited the formation of amorphous aggregates but promoted the formation of amyloid aggregates in a p53C R175H mutant. The salts exhibited different effects against the wild-type and R175H mutants of p53C. However, the ratio of ANS/ThT fluorescence for the wild-type and R175H mutant remained constant. KCl also suppressed the structural transition and loss of the DNA-binding function of p53C. These observations indicate the existence of multiple steps of p53C aggregation, probably coupled with the dissociation of Zn. Notably, amorphous aggregates and amyloid aggregates have distinct properties that could be discriminated by various small additives upon aggregation.

    DOI: 10.3389/fmolb.2022.869851

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  7. A cryptic phosphate-binding pocket on the SPFH domain of human stomatin that regulates a novel fibril-like self-assembly.

    Kataoka K, Suzuki S, Tenno T, Goda N, Hibino E, Oshima A, Hiroaki H

    Current research in structural biology   4 巻   頁: 158 - 166   2022年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Current Research in Structural Biology  

    Human stomatin (hSTOM) is a component of the membrane skeleton of erythrocytes that maintains the membrane's shape and stiffness through interconnecting spectrin and actin. hSTOM is a member of the protein family that possesses a single stomatin/prohibitin/flotillin/HflK (SPFH) domain at the center of the molecule. Although SPFH domain proteins are widely distributed from archaea to mammals, the detailed function of the domain remains unclear. In this study, we first determined the solution structure of the SPFH domain of hSTOM (hSTOM(SPFH)) via NMR. The solution structure of hSTOM(SPFH) is essentially identical to the already reported crystal structure of the STOM SPFH domain (mSTOM(SPFH)) of mice, except for the existence of a small hydrophilic pocket on the surface. We identified this pocket as a phosphate-binding site by comparing its NMR spectra with and without phosphate ions. Meanwhile, during the conventional process of protein NMR analysis, we eventually discovered that hSTOM(SPFH) formed a unique solid material after lyophilization. This lyophilized hSTOM(SPFH) sample was moderately slowly dissolved in a physiological buffer. Interestingly, it was resistant to dissolution against the phosphate buffer. We then found that the lyophilized hSTOM(SPFH) formed a fibril-like assembly under electron microscopy. Finally, we succeeded in reproducing this fibril-like assembly of hSTOM(SPFH) using a centrifugal ultrafiltration device, thus demonstrating that the increased protein concentration may promote self-assembly of hSTOM(SPFH) into fibril forms. Our observations may help understand the molecular function of the SPFH domain and its involvement in protein oligomerization as a component of the membrane skeleton. (245 words).

    DOI: 10.1016/j.crstbi.2022.05.002

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  8. Announcing the call for the Special Issue on "The Australian Society for Biophysics (ASB) - 2021 Meeting".

    Cranfield C, Whelan D, Cox C, Shearwin K, Ho J, Allen T, Shibuya R, Hibino E, Hayashi K, Dos Remedios C, Li A

    Biophysical reviews   13 巻 ( 4 ) 頁: 485 - 486   2021年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Biophysical Reviews  

    This Commentary describes a call for submissions for the upcoming Special Issue focused on the research topics presented at the Australian Society of Biophysics (ASB) in 2020 and 2021. Submissions from past and present ASB members who could not attend these meetings are also welcome as contributions to this special issue.

    DOI: 10.1007/s12551-021-00813-w

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  9. Extracellular Release of ILEI/FAM3C and Amyloid-beta Is Associated with the Activation of Distinct Synapse Subpopulations

    Nakano Masaki, Mitsuishi Yachiyo, Liu Lei, Watanabe Naoki, Hibino Emi, Hata Saori, Saito Takashi, Saido Takaomi C., Murayama Shigeo, Kasuga Kensaku, Ikeuchi Takeshi, Suzuki Toshiharu, Nishimura Masaki

    JOURNAL OF ALZHEIMERS DISEASE   80 巻 ( 1 ) 頁: 159 - 174   2021年

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Journal of Alzheimer's disease : JAD  

    BACKGROUND: Brain amyloid-β (Aβ) peptide is released into the interstitial fluid (ISF) in a neuronal activity-dependent manner, and Aβ deposition in Alzheimer's disease (AD) is linked to baseline neuronal activity. Although the intrinsic mechanism for Aβ generation remains to be elucidated, interleukin-like epithelial-mesenchymal transition inducer (ILEI) is a candidate for an endogenous Aβ suppressor. OBJECTIVE: This study aimed to access the mechanism underlying ILEI secretion and its effect on Aβ production in the brain. METHODS: ILEI and Aβ levels in the cerebral cortex were monitored using a newly developed ILEI-specific ELISA and in vivo microdialysis in mutant human Aβ precursor protein-knockin mice. ILEI levels in autopsied brains and cerebrospinal fluid (CSF) were measured using ELISA. RESULTS: Extracellular release of ILEI and Aβ was dependent on neuronal activation and specifically on tetanus toxin-sensitive exocytosis of synaptic vesicles. However, simultaneous monitoring of extracellular ILEI and Aβ revealed that a spontaneous fluctuation of ILEI levels appeared to inversely mirror that of Aβ levels. Selective activation and inhibition of synaptic receptors differentially altered these levels. The evoked activation of AMPA-type receptors resulted in opposing changes to ILEI and Aβ levels. Brain ILEI levels were selectively decreased in AD. CSF ILEI concentration correlated with that of Aβ and were reduced in AD and mild cognitive impairment. CONCLUSION: ILEI and Aβ are released from distinct subpopulations of synaptic terminals in an activity-dependent manner, and ILEI negatively regulates Aβ production in specific synapse types. CSF ILEI might represent a surrogate marker for the accumulation of brain Aβ.

    DOI: 10.3233/JAD-201174

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  10. FAM3C in Alzheimer's disease. A risk-related molecule and potential therapeutic target. 査読有り

    Nishimura M, Watanabe N, Mitsuishi Y, Hibino E, Nakano M, Liu L, Sugi T

    Neuroscience of Dementia     頁: in press   2020年

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    記述言語:英語  

  11. A novel mode of interaction between intrinsically disordered proteins

    Hibino Emi, Hoshino Masaru

    BIOPHYSICS AND PHYSICOBIOLOGY   17 巻 ( 0 ) 頁: 86 - 93   2020年

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Biophysics and physicobiology  

    An increasing number of proteins, which have neither regular secondary nor well-defined tertiary structures, have been found to be present in cells. The structure of these proteins is highly flexible and disordered under physiological (native) conditions, and they are called “intrinsically disordered” proteins (IDPs). Many of the IDPs are involved in interactions with other biomolecules such as DNA, RNA, carbohydrates, and proteins. While these IDPs are largely unstructured by themselves, marked conformational changes often occur upon binding to an interacting partner, which is known as the “coupled folding and binding mechanism”, which enable them to change the conformation to become compatible with the shape of the multiple target biomolecules. We have studied the structure and interaction of eukaryotic transcription factors Sp1 and TAF4, and found that both of them have long intrinsically disordered regions (IDRs). One of the IDRs in Sp1 exhibited homo-oligomer formation. In addition, the same region was used for the interaction with another IDR found in the TAF4 molecule. In both cases, we have not detected any significant conformational change in that region, suggesting a prominent and novel binding mode for IDPs/IDRs, which are not categorized by the well-accepted concept of the coupled folding and binding mechanism.

    DOI: 10.2142/biophysico.BSJ-2020012

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  12. Lipid class composition of membrane and raft fractions from brains of individuals with Alzheimer's disease 国際誌

    Kawatsuki Akihiro, Morita Shin-ya, Watanabe Naoki, Hibino Emi, Mitsuishi Yachiyo, Sugi Takuma, Murayama Shigeo, Nishimura Masaki

    BIOCHEMISTRY AND BIOPHYSICS REPORTS   20 巻 ( 100704 ) 頁: 100704 - 100704   2019年12月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Biochemistry and Biophysics Reports  

    Perturbation of the homeostasis of brain membrane lipids has been implicated in the pathomechanism of Alzheimer's disease (AD). The ε4 allele of the apolipoprotein E gene (APOE) confers an increased risk, in a dosage-dependent manner, for brain amyloid-β accumulation and the development of sporadic AD. An effect of the APOE genotype on brain lipid homeostasis may underlie the AD risk associated with the ε4 allele. In this research, we examined an effect of APOE ε4 on the lipid class composition of crude membranes and raft-enriched fractions of brains. We applied enzymatic reaction-based methods for the quantification of phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidic acid, and sphingomyelin. Our results indicate that brain lipid class composition was neither significantly altered in AD subjects nor affected by the presence of the APOE ε4 allele.

    DOI: 10.1016/j.bbrep.2019.100704

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  13. 大脳皮質におけるILEI/FAM3CおよびAβの間質液への分泌様式に関する比較検討 査読有り

    中野 将希, 三ツ石 弥千代, 渡邊 直希, 日比野 絵美, 斉藤 貴志, 西道 隆臣, 鈴木 利治, 西村 正樹

    Dementia Japan   33 巻 ( 4 ) 頁: 514 - 514   2019年10月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:(一社)日本認知症学会  

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  14. 天然変性タンパク質の新しい相互作用機構

    日比野 絵美, 星野 大

    生物物理   59 巻 ( 4 ) 頁: 202 - 204   2019年

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:一般社団法人 日本生物物理学会  

    DOI: 10.2142/biophys.59.202

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  15. Identification of heteromolecular binding sites in transcription factors Sp1 and TAF4 using high-resolution nuclear magnetic resonance spectroscopy

    Hibino Emi, Inoue Rintaro, Sugiyama Masaaki, Kuwahara Jun, Matsuzaki Katsumi, Hoshino Masaru

    PROTEIN SCIENCE   26 巻 ( 11 ) 頁: 2280 - 2290   2017年11月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Protein Science  

    The expression of eukaryotic genes is precisely controlled by interactions between general transcriptional factors and promoter-specific transcriptional activators. The fourth element of TATA-box binding protein-associated factor (TAF4), an essential subunit of the general transcription factor TFIID, serves as a coactivator for various promoter-specific transcriptional regulators. Interactions between TAF4 and site-specific transcriptional activators, such as Sp1, are important for regulating the expression levels of genes of interest. However, only limited information is available on the molecular mechanisms underlying the interactions between these transcriptional regulatory proteins. We herein analyzed the interaction between the transcriptional factors Sp1 and TAF4 using high-resolution solution nuclear magnetic resonance spectroscopy. We found that four glutamine-rich (Q-rich) regions in TAF4 were largely disordered under nearly physiological conditions. Among them, the first Q-rich region in TAF4 was essential for the interaction with another Q-rich region in the Sp1 molecule, most of which was largely disordered. The residues responsible for this interaction were specific and highly localized in a defined region within a range of 20–30 residues. Nevertheless, a detailed analysis of 13C-chemical shift values suggested that no significant conformational change occurred upon binding. These results indicate a prominent and exceptional binding mode for intrinsically disordered proteins other than the well-accepted concept of “coupled folding and binding.”.

    DOI: 10.1002/pro.3287

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  16. Interaction between intrinsically disordered regions in transcription factors Sp1 and TAF4.

    Hibino E, Inoue R, Sugiyama M, Kuwahara J, Matsuzaki K, Hoshino M

    Protein science : a publication of the Protein Society   25 巻 ( 11 ) 頁: 2006 - 2017   2016年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Protein Science  

    The expression of eukaryotic genes is precisely controlled by specific interactions between general transcription initiation factors and gene-specific transcriptional activators. The general transcription factor TFIID, which plays an essential role in mediating transcriptional activation, is a multisubunit complex comprising the TATA box-binding protein (TBP) and multiple TBP-associated factors (TAFs). On the other hand, biochemical and genetic approaches have shown that the promoter-specific transcriptional activator Sp1 has the ability to interact with one of the components of TFIID, the TBP-associated factor TAF4. We herein report the structural details of the glutamine-rich domains (Q-domains) of Sp1 and TAF4 using circular dichroism (CD) and heteronuclear magnetic resonance (NMR) spectroscopy. We found that the two Q-domains of Sp1 and four Q-domains of TAF4 were disordered under physiological conditions. We also quantitatively analyzed the interaction between the Q-domains of Sp1 and TAF4 by NMR and surface plasmon resonance, and detected a weak but specific association between them. Nevertheless, a detailed analysis of CD spectra suggested that any significant conformational change did not occur concomitantly with this association, at least at the level of the overall secondary structure. These results may represent a prominent and exceptional binding mode for the IDPs, which are not categorized in a well-accepted concept of “coupled folding and binding.”.

    DOI: 10.1002/pro.3013

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  17. Interaction between isolated transcriptional activation domains of Sp1 revealed by heteronuclear magnetic resonance.

    Hiramatsu N, Hibino E, Matsuzaki K, Kuwahara J, Hoshino M

    Protein science : a publication of the Protein Society   21 巻 ( 10 ) 頁: 1481 - 8   2012年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Protein Science  

    The promoter-specific transcription factor Sp1 is expressed ubiquitously, and plays a primary role in the regulation of the expression of many genes. Domains A and B located in the N-terminal half of the protein are characterized by glutamine-rich (Q-rich) sequences. These Q-rich domains have been shown to be involved in the interaction between Sp1 and different classes of nuclear proteins, such as TATA-binding protein associated factors. Furthermore, the selfassociation of Sp1 via Q-rich domains is also important for the regulation of transcriptional activity. It has been considered that an Sp1 molecule bound to a "distal" GC-box synergistically interacts with another Sp1 molecule at a "proximal" binding site. Although the formation of multimers via Q-rich domains seems functionally important for Sp1, little is known about the structural and physicochemical nature of the interaction between Q-rich domains. We analyzed the structural details of isolated glutamine-rich B (QB) domains of Sp1 by circular dichroism (CD), analytical ultracentrifugation, and heteronuclear magnetic resonance spectroscopy (NMR). We found the isolated QB domains to be disordered under all conditions examined. Nevertheless, a detailed analysis of NMR spectra clearly indicated interaction between the domains. In particular, the C-terminal half was responsible for the self-association. Furthermore, analytical ultracentrifugation demonstrated weak but significant interaction between isolated QB domains. The self-association between QB domains would be responsible, at least in part, for the formation of multimers by full-length Sp1 molecules that has been proposed to occur during transcriptional activation. © 2012 The Protein Society.

    DOI: 10.1002/pro.2137

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▼全件表示

MISC 1

  1. Glutamine-rich activation domain of transcription factor Sp1-biochemical activity and structure

    Jun Kuwahara, Chisana Uwatoko, Emi Hibino, Katsumi Matsuzaki, Masaru Hoshino  

    PROTEIN SCIENCE24 巻   頁: 312 - 312   2015年10月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:WILEY-BLACKWELL  

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講演・口頭発表等 15

  1. Aβ産生抑制タンパク質ILEIの活性中心の同定

    日比野 絵美, 西村正樹

    第58回日本生物物理学会年会  2020年9月16日 

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    開催年月日: 2020年9月

    記述言語:英語   会議種別:ポスター発表  

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  2. The interaction between transcription factors Sp1 and TAF4 via the intrinsically disordered regions. 国際会議

    The 9th SKO Symposium Program 

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    開催年月日: 2015年11月

    記述言語:英語   会議種別:口頭発表(一般)  

    国名:大韓民国  

  3. 転写因子Sp1とTAF4の天然変性領域を介した相互作用 招待有り

    日比野 絵美, 井上 倫太郎, 杉山 正明, 桑原 淳, 松崎 勝巳, 星野 大

    第52回日本生物物理学会年会 

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    開催年月日: 2014年9月

    記述言語:英語   会議種別:口頭発表(招待・特別)  

    開催地:札幌   国名:日本国  

  4. 転写因子Sp1とTAF4の天然変性領域を介した相互作用の解析

    日比野 絵美, 桑原 淳, 松崎 勝巳, 星野 大

    第13回日本蛋白質科学会年会  

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    開催年月日: 2013年6月

    記述言語:日本語   会議種別:ポスター発表  

    開催地:鳥取   国名:日本国  

  5. 特異な機序でアミロイドβ産生を抑制するILEI / FAM3Cとアルツハイマー病リスク

    日比野 絵美, 渡辺 直希, 西村 正樹

    第91回日本生化学会大会  2018年9月 

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    記述言語:日本語   会議種別:シンポジウム・ワークショップ パネル(公募)  

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  6. 天然変性領域間の相互作用の物理化学的解析

    日比野 絵美

    蛋白質異常凝集研究会  2017年12月 

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    記述言語:日本語   会議種別:口頭発表(一般)  

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  7. The interaction between transcription factors Sp1 and TAF4 via the intrinsically disordered regions. 国際会議

    日比野 絵美, 井上 倫太郎, 杉山 正明, 桑原 淳, 松崎 勝巳, 星野 大

    The 9th SKO Symposium Program  2015年11月 

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    記述言語:英語   会議種別:口頭発表(一般)  

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  8. Structure-based analysis of ILEI/FAM3C activity to inhibit Aβ generation

    ◯Emi Hibino, Masatake Sugita, Yachiyo Mitsuishi, Naoki Watanabe, Masaki Nakano, Takuma Sugi, Masaki Nishimura

    第56回日本生物物理学会年会  2018年9月 

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    記述言語:英語   会議種別:口頭発表(一般)  

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  9. ILEI/FAM3C Suppresses Amyloid-β Generation by a Unique Mechanism 国際会議

    日比野 絵美

    第24回MNRC国際シンポジウム  2018年9月 

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    記述言語:英語   会議種別:シンポジウム・ワークショップ パネル(指名)  

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  10. Aβ産生抑制タンパク質ILEIの構造解析に基づく機能メカニズムの検討

    日比野 絵美

    第36回日本認知症学会学術集会  2017年11月 

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    記述言語:日本語   会議種別:ポスター発表  

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  11. Aβ産生抑制タンパク質ILEIの構造と機能の解析

    日比野 絵美

    2017年度生命科学系学会合同年次大会  2017年12月 

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    記述言語:英語   会議種別:ポスター発表  

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  12. 転写因子Sp1とTAF4の天然変性領域を介した相互作用 招待有り

    日比野 絵美, 井上 倫太郎, 杉山 正明, 桑原 淳, 松崎 勝巳, 星野 大

    第52回日本生物物理学会年会  2014年9月 

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    記述言語:英語   会議種別:口頭発表(招待・特別)  

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  13. 転写因子Sp1とTAF4の天然変性領域を介した相互作用の解析

    日比野 絵美, 桑原 淳, 松崎 勝巳, 星野 大

    第13回日本蛋白質科学会年会  2013年6月 

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    記述言語:日本語   会議種別:ポスター発表  

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  14. グリチルリチンとタイト結合裏打ちタンパク質ZO1-PDZ1ドメインとの結合解析

    日比野絵美, 久田美咲, 合田名都子, 天野剛志, 廣明秀一

    令和2年度 生物物理中部支部講演会  2021年3月 

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    記述言語:英語   会議種別:口頭発表(一般)  

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  15. グリチルリチンのタイト結合裏打ちタンパク質ZO1 PDZ1ドメインへの結合構造の解析

    日比野絵美, 久田美咲, 合田名都子, 天野剛志, 廣明秀一

    日本薬学会第141年会  2021年3月 

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    記述言語:英語   会議種別:口頭発表(一般)  

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▼全件表示

共同研究・競争的資金等の研究課題 4

  1. 亜鉛イオン含有がん抑制タンパク質p53のアミロイド凝集体解析

    2022年 - 2024年3月

    2022年度研究助成 

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    資金種別:競争的資金

    配分額:800000円 ( 直接経費:800000円 )

  2. がん抑制タンパク質p53のアミロイド形成機構の原子レベル解析

    2022年 - 2024年3月

    令和4年度 学術・みらい助成 

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    担当区分:研究代表者  資金種別:競争的資金

    配分額:300000円 ( 直接経費:300000円 )

  3. がん抑制タンパク質p53の凝集制御法の確立

    2022年 - 2023年3月

    研究奨励金 

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    担当区分:研究代表者  資金種別:競争的資金

    配分額:2000000円 ( 直接経費:2000000円 )

  4. がん抑制タンパク質p53の機能喪失につながる新規機構解明

    2021年 - 2022年3月

    がんその他の悪性新生物研究助成金 

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    担当区分:研究代表者  資金種別:競争的資金

    配分額:500000円 ( 直接経費:500000円 )

科研費 1

  1. アミロイドβタンパク質産生を特異的に抑制する新たな機序の解析

    研究課題/研究課題番号:18K14883  2018年4月 - 2022年3月

    科学研究費助成事業  若手研究

    日比野絵美

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    担当区分:研究代表者 

    配分額:4160000円 ( 直接経費:3200000円 、 間接経費:960000円 )

    アルツハイマー病はアミロイドβタンパク質 (Aβ) の脳内蓄積が原因とされている。分泌タンパク質ILEIはγセクレターゼの構成分子の一つであるプレセニリン-1へ結合することでAβおよびAβの前駆体であるAPP-CTFの産生を抑制することが報告されている。加えて、ILEIはγセクレターゼに結合するものの、γセクレターゼの活性自体には影響を与えないことから、新規のメカニズムによる機能であることもわかっているが、詳細なメカニズムは未解明のままである。本研究の目的は、ILEIのAβ産生抑制機能に関わる構造―機能連関を明らかにし、アルツハイマー病治療薬の開発へつなげることである。
    培養細胞を用いたアラニンスキャニングの系により、ILEIの機能に関与する残基を特定する計画としていた。そこで実際にアラニンスキャニングを実施し、機能を喪失するアラニン変異体を得ることができた。しかし、NMR解析の結果、その変異体はfold-unfoldの平衡にあることが判明した。そこで研究の方針を、タンパク質の構造解析により結合に関与する残基を特定してから培養細胞の系で確認することに切り替えた。溶液NMR解析により、これまで明確に示せていなかったILEIとγセクレターゼの直接結合が確認できた。またγセクレターゼ側の候補構造を、ドッキングシミュレーションにより算出した。その構造の妥当性を検証するため、まずILEIの3次元NMR測定を行い、帰属することでILEI側のγセクレターゼとの結合部位を明らかにする。くわえて、既に構築した培養細胞でのILEIの機能評価系により、裏付ける。本研究は、アルツハイマー病の治療・予防薬のStructure-Based Drug Design (SBDD) の土台につながる。
    昨年度までに、ILEIのAβ産生抑制機能を培養細胞を用いて評価するアラニンスキャニング系を構築した。その評価系を用いて機能に重要なアミノ酸残基の同定を試みた。候補残基が得られたため、アラニン変異体のNMRスペクトルを取得したところ、野生型の構造が保たれていなかったことが判明した。このことから、培養細胞からのアプローチでは不十分であることが判明した。そこでタンパク質構造からのアプローチを先に取ることとした。まずドッキングシミュレーションによりILEIとγセクレターゼ複合体構造の候補が複数挙げられた。この中からもっとも妥当な構造を得るために、ILEI側の複合体形成に重要な残基をNMR解析により明らかにすることとした。これまで確認できていなかったILEIとγセクレターゼの直接結合が示せ、γセクレターぜ複合体形成に関与するピークが複数得られたため、ILEIの3次元NMR測定を実施し、残基を特定するところである。
    培養細胞系で機能に重要なアミノ酸残基を同定する予定であったが、その点に関しては予定通り進行しなかった。一方で、これまでILEIの変異導入による構造不安定性は示唆されていたものの、実態については不明であった。今回の結果から、変性状態とフォールド状態の平衡にあることが判明した。当初の計画どおりには進展しなかったもののそれに伴い新たな知見が得られ、計画の方針を切り替えてからは順調に進行しているため、総合して概ね順調に進展しているとした。
    ドッキングシミュレーションで得られた複合体構造を、NMR解析と培養細胞の実験でもっとも妥当な構造を特定する。その結果、アルツハイマー病の治療・予防薬のStructure-Based Drug Design(SBDD)の土台につながる。今後は、この複合体構造を基に、ドラッグデザインへ展開していきたいと考えている。また、本研究成果に関し論文化する。

 

担当経験のある科目 (本学以外) 1

  1. 生理学

    京都文化医療専門学校)

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社会貢献活動 1

  1. 第3回 滋賀ジュニアリサーチグラント成果発表会

    役割:助言・指導

    リバネス  2020年2月

学術貢献活動 3

  1. 第2回CIBoGリトリート(第13回NAGOYAグローバルリトリート)

    2021年1月

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    種別:大会・シンポジウム等 

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  2. 第3回滋賀ジュニアリサーチグラント成果発表会

    役割:審査・評価

    株式会社リバネス  2020年2月

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    種別:大会・シンポジウム等 

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  3. サイエンスキャッスル2019関西大会

    役割:審査・評価

    株式会社リバネス  2019年12月

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    種別:大会・シンポジウム等 

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