Updated on 2022/04/21

写真a

 
HIBINO Emi
 
Organization
Graduate School of Pharmaceutical Sciences Department of Basic Medicinal Sciences Structural Biology Assistant Professor
Title
Assistant Professor
Contact information
メールアドレス
External link

Degree 1

  1. 博士 (薬科学) ( 2017.3   京都大学 ) 

Research Interests 6

  1. intrinsically disordered proteins

  2. protein interaction

  3. Alzheimer's disease

  4. p53

  5. NMR

  6. アミロイド

Research Areas 2

  1. Life Science / Biophysics

  2. Life Science / Pharmaceutical analytical chemistry and physicochemistry

Current Research Project and 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

Research History 4

  1. Nagoya University   graduate School of Pharmaceutical Science   Assistant Professor

    2022.4

  2. Shiga University of Medical Science   Molecular Neuroscience Research Center

    2020.6

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  3. Nagoya University   graduate School of Pharmaceutical Science   Designated assistant professor

    2020.6 - 2022.3

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  4. Shiga University of Medical Science   Designated assistant professor

    2017.4 - 2020.5

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    Country:Japan

Education 2

  1. 京都大学大学院   薬学研究科

    2011.4 - 2017.3

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  2. Kyoto University   Faculty of Pharmaceutical Sciences

    2007.4 - 2011.3

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Professional Memberships 5

  1. 日本生化学会

  2. 日本生物物理学会

  3. PROTEIN SCIENCE SOCIETY OF JAPAN

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  4. 日本核磁気共鳴学会

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  5. 日本薬学会

 

Papers 14

  1. 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   Vol. 14 ( 1 ) page: 1 - 2   2022.2

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher: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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  2. Bex1 is essential for ciliogenesis and harbours biomolecular condensate-forming capacity

    Hibino Emi, Ichiyama Yusuke, Tsukamura Atsushi, Senju Yosuke, Morimune Takao, Ohji Masahito, Maruo Yoshihiro, Nishimura Masaki, Mori Masaki

    BMC BIOLOGY   Vol. 20 ( 1 ) page: 42   2022.2

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    Language:Japanese   Publishing type:Research paper (scientific journal)   Publisher: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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  3. 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 Emi, Goda Natsuko, Hisada Misaki, Tenno Takeshi, Hiroaki Hidekazu

    FOOD & FUNCTION     2022.1

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    Language:Japanese   Publishing type:Research paper (scientific journal)  

    DOI: 10.1039/d1fo03062k

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

    Hibino E., Hiroaki H.

    Biophysical Reviews     2022

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    Language:Japanese   Publishing type:Research paper (scientific journal)   Publisher: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. 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   Vol. 13 ( 4 ) page: 1 - 2   2021.6

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher: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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  6. Extracellular Release of ILEI/FAM3C and Amyloid-β Is Associated with the Activation of Distinct Synapse Subpopulations

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

    Journal of Alzheimer's Disease   Vol. 80 ( 1 ) page: 159 - 174   2021

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:IOS Press  

    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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  7. FAM3C in Alzheimer's disease. A risk-related molecule and potential therapeutic target. Reviewed

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

    Neuroscience of Dementia     page: in press   2020

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  8. A novel mode of interaction between intrinsically disordered proteins

    Hibino Emi, Hoshino Masaru

    Biophysics and Physicobiology   Vol. 17 ( 0 ) page: 86 - 93   2020

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    Language:Japanese   Publishing type:Research paper (scientific journal)   Publisher:The Biophysical Society of Japan  

    <p>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.</p>

    DOI: 10.2142/biophysico.BSJ-2020012

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  9. Lipid class composition of membrane and raft fractions from brains of individuals with Alzheimer's disease. International journal

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

    Biochemistry and biophysics reports   Vol. 20 ( 100704 ) page: 100704 - 100704   2019.12

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    Language:English   Publishing type:Research paper (scientific journal)  

    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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  10. 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 Reviewed

    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   Vol. 33 ( 4 ) page: 514 - 514   2019.10

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    Language:Japanese   Publishing type:Research paper (scientific journal)   Publisher:(一社)日本認知症学会  

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  11. Novel Interaction Mechanism between the Intrinsically Disordered Proteins

    HIBINO Emi, HOSHINO Masaru

    Seibutsu Butsuri   Vol. 59 ( 4 ) page: 202 - 204   2019

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    Language:Japanese   Publishing type:Research paper (scientific journal)   Publisher:The Biophysical Society of Japan General Incorporated Association  

    DOI: 10.2142/biophys.59.202

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

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

    PROTEIN SCIENCE   Vol. 26 ( 11 ) page: 2280 - 2290   2017.11

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    Language:Japanese   Publishing type:Research paper (scientific journal)   Publisher:WILEY  

    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 C-13-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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  13. Interaction between intrinsically disordered regions in transcription factors Sp1 and TAF4

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

    PROTEIN SCIENCE   Vol. 25 ( 11 ) page: 2006 - 2017   2016.11

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    Language:Japanese   Publishing type:Research paper (scientific journal)   Publisher:WILEY-BLACKWELL  

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

    Naoko Hiramatsu, Emi Hibino, Katsumi Matsuzaki, Jun Kuwahara, Masaru Hoshino

    PROTEIN SCIENCE   Vol. 21 ( 10 ) page: 1481 - 1488   2012.10

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    Language:Japanese   Publishing type:Research paper (scientific journal)   Publisher:WILEY-BLACKWELL  

    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 self-association 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.

    DOI: 10.1002/pro.2137

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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 SCIENCE   Vol. 24   page: 312 - 312   2015.10

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    Language:English   Publishing type:Research paper, summary (international conference)   Publisher:WILEY-BLACKWELL  

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Presentations 15

  1. Active center of Aβ production repressor ILEI/FAM3C

    ○Emi Hibino, Masaki Nishimura

    The 58th Annual Meeting of the Biophysical Society of Japan  2020.9.16 

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    Event date: 2020.9

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  2. The interaction between transcription factors Sp1 and TAF4 via the intrinsically disordered regions. International conference

    The 9th SKO Symposium Program 

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    Event date: 2015.11

    Language:English   Presentation type:Oral presentation (general)  

    Country:Korea, Republic of  

  3. 転写因子Sp1とTAF4の天然変性領域を介した相互作用 Invited

    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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    Event date: 2014.9

    Language:English   Presentation type:Oral presentation (invited, special)  

    Venue:札幌   Country:Japan  

  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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    Event date: 2013.6

    Language:Japanese   Presentation type:Poster presentation  

    Venue:鳥取   Country:Japan  

  5. 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  2013.6 

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  6. 転写因子Sp1とTAF4の天然変性領域を介した相互作用 Invited

    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  2014.9 

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  7. Risk for Alzheimer's disease and ILEI/FAM3C that suppresses amyloid-β generation by a unique mechanism

    ◯Emi Hibino, Naoki Watanabe, Masaki Nishimura

    The 91st Annual Meeting of the Japanese Biochemical Society  2018.9 

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  8. 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  2017.12 

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  9. The interaction between transcription factors Sp1 and TAF4 via the intrinsically disordered regions. International conference

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

    The 9th SKO Symposium Program  2015.11 

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  10. 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

    The 56th Annual Meeting of The Biophysical Society of Japan  2018.9 

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  11. ILEI/FAM3C Suppresses Amyloid-β Generation by a Unique Mechanism International conference

    Emi Hibino

    24th MNRC International symposium  2018.9 

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  12. 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  2017.11 

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  13. ILEI/FAM3C represses Aβ production: structural and functional properties

    Emi Hibino

    ConBio2017  2017.12 

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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  2021.3 

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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  2021.3 

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KAKENHI (Grants-in-Aid for Scientific Research) 2

  1. 転移因子と天然変性タンパク質によるクロマチン高次構造構築原理の解明

    2021.9 - 2022.3

    名古屋大学  令和3年度NU部局横断イノベーション創出プロジェクト 

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    Authorship:Coinvestigator(s)  Grant type:Competitive

    Direct Cost: \1000000 )

  2. 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

    Grant number:18K14883  2018.4 - 2022.3

    科学研究費助成事業  若手研究

    日比野絵美

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    Authorship:Principal investigator 

    Grant amount:\4160000 ( Direct Cost: \3200000 、 Indirect Cost:\960000 )

    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。

 

Teaching Experience (Off-campus) 1

  1. 生理学

    京都文化医療専門学校)

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Social Contribution 1

  1. 第3回 滋賀ジュニアリサーチグラント成果発表会

    Role(s):Advisor

    リバネス  2020.2

Academic Activities 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)

    2021.1

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    Type:Competition, symposium, etc. 

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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

    Role(s):Review, evaluation

    株式会社リバネス  2020.2

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  3. サイエンスキャッスル2019関西大会

    Role(s):Review, evaluation

    株式会社リバネス  2019.12

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    Type:Competition, symposium, etc. 

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