横川　真梨子 (ヨコガワ　マリコ)

Yokogawa, Mariko

写真a

所属（所属キャンパス）

薬学部 薬科学科 生命機能物理学講座 （芝共立）

職名

専任講師

外部リンク
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学位 【 表示 ／ 非表示 】

  • 博士（薬学）, 東京大学, 課程

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免許・資格 【 表示 ／ 非表示 】

  • 薬剤師免許

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研究分野 【 表示 ／ 非表示 】

  • ライフサイエンス / 薬系分析、物理化学

  • ライフサイエンス / 構造生物化学

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研究キーワード 【 表示 ／ 非表示 】

  • NMR

  • イオンチャネル

  • 構造生物学

  • 膜タンパク質

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著書 【 表示 ／ 非表示 】

  • Peptide Toxins Targeting KV Channels

    Matsumura K., Yokogawa M., Osawa M., Handbook of Experimental Pharmacology, 2021年

    　概要を見る

    A number of peptide toxins isolated from animals target potassium ion (K+) channels. Many of them are particularly known to inhibit voltage-gated K+ (KV) channels and are mainly classified into pore-blocking toxins or gating-modifier toxins. Pore-blocking toxins directly bind to the ion permeation pores of KV channels, thereby physically occluding them. In contrast, gating-modifier toxins bind to the voltage-sensor domains of KV channels, modulating their voltage-dependent conformational changes. These peptide toxins are useful molecular tools in revealing the structure-function relationship of KV channels and have potential for novel treatments for diseases related to KV channels. This review focuses on the inhibition mechanism of pore-blocking and gating-modifier toxins that target KV channels.

  • Nuclear magnetic resonance approaches for characterizing protein-protein interactions

    Toyama Y., Mase Y., Kano H., Yokogawa M., Osawa M., Shimada I., Methods in Molecular Biology, 2018年

    　概要を見る

    The gating of potassium ion (K+) channels is regulated by various kinds of protein-protein interactions (PPIs). Structural investigations of these PPIs provide useful information not only for understanding the gating mechanisms of K+ channels, but also for developing the pharmaceutical compounds targeting K+ channels. Here, we describe a nuclear magnetic resonance spectroscopic method, termed the cross saturation (CS) method, to accurately determine the binding surfaces of protein complexes, and its application to the investigation of the interaction between a G protein-coupled inwardly rectifying K+ channel and a G protein α subunit.

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論文 【 表示 ／ 非表示 】

  • Paip2A inhibits translation by competitively binding to the RNA recognition motifs of PABPC1 and promoting its dissociation from the poly(A) tail.

    Sagae T, Yokogawa M, Sawazaki R, Ishii Y, Hosoda N, Hoshino SI, Imai S, Shimada I, Osawa M

    The Journal of biological chemistry （Journal of Biological Chemistry)  298 （ 5 ） 101844 2022年03月

    ISSN  0021-9258

    　概要を見る

    Eukaryotic mRNAs possess a poly(A) tail at their 30-end, to which poly(A)-binding protein C1 (PABPC1) binds and recruits other proteins that regulate translation. Enhanced poly(A)dependent translation, which is also PABPC1 dependent, promotes cellular and viral proliferation. PABP-interacting protein 2A (Paip2A) effectively represses poly(A)-dependent translation by causing the dissociation of PABPC1 from the poly(A) tail; however, the underlying mechanism remains unknown. This study was conducted to investigate the functional mechanisms of Paip2A action by characterizing the PABPC1–poly(A) and PABPC1–Paip2A interactions. Isothermal titration calorimetry and NMR analyses indicated that both interactions predominantly occurred at the RNA recognition motif (RRM) 2–RRM3 regions of PABPC1, which have comparable affinities for poly(A) and Paip2A (dissociation constant, Kd = 1 nM). However, the Kd values of isolated RRM2 were 200 and 4 μM in their interactions with poly(A) and Paip2A, respectively; Kd values of 5 and 1 μM were observed for the interactions of isolated RRM3 with poly(A) and Paip2A, respectively. NMR analyses also revealed that Paip2A can bind to the poly(A)binding interfaces of the RRM2 and RRM3 regions of PABPC1. Based on these results, we propose the following functional mechanism for Paip2A: Paip2A initially binds to the RRM2 region of poly(A)-bound PABPC1, and RRM2-anchored Paip2A effectively displaces the RRM3 region from poly(A), resulting in dissociation of the whole PABPC1 molecule. Together, our findings provide insight into the translation repression effect of Paip2A and may aid in the development of novel anticancer and/or antiviral drugs.

  • Mechanism of hERG inhibition by gating-modifier toxin, APETx1, deduced by functional characterization

    Matsumura K., Shimomura T., Kubo Y., Oka T., Kobayashi N., Imai S., Yanase N., Akimoto M., Fukuda M., Yokogawa M., Ikeda K., Kurita J.i., Nishimura Y., Shimada I., Osawa M.

    BMC Molecular and Cell Biology （BMC Molecular and Cell Biology)  22 （ 3 ） 3 2021年01月

    研究論文（学術雑誌）, 共著, 査読有り

    　概要を見る

    Background: Human ether-à-go-go-related gene potassium channel 1 (hERG) is a voltage-gated potassium channel, the voltage-sensing domain (VSD) of which is targeted by a gating-modifier toxin, APETx1. APETx1 is a 42-residue peptide toxin of sea anemone Anthopleura elegantissima and inhibits hERG by stabilizing the resting state. A previous study that conducted cysteine-scanning analysis of hERG identified two residues in the S3-S4 region of the VSD that play important roles in hERG inhibition by APETx1. However, mutational analysis of APETx1 could not be conducted as only natural resources have been available until now. Therefore, it remains unclear where and how APETx1 interacts with the VSD in the resting state. Results: We established a method for preparing recombinant APETx1 and determined the NMR structure of the recombinant APETx1, which is structurally equivalent to the natural product. Electrophysiological analyses using wild type and mutants of APETx1 and hERG revealed that their hydrophobic residues, F15, Y32, F33, and L34, in APETx1, and F508 and I521 in hERG, in addition to a previously reported acidic hERG residue, E518, play key roles in the inhibition of hERG by APETx1. Our hypothetical docking models of the APETx1-VSD complex satisfied the results of mutational analysis. Conclusions: The present study identified the key residues of APETx1 and hERG that are involved in hERG inhibition by APETx1. These results would help advance understanding of the inhibitory mechanism of APETx1, which could provide a structural basis for designing novel ligands targeting the VSDs of KV channels.

  • Structural mechanism underlying G protein family-specific regulation of G protein-gated inwardly rectifying potassium channel

    Kano H., Toyama Y., Imai S., Iwahashi Y., Mase Y., Yokogawa M., Osawa M., Shimada I.

    Nature Communications 10 （ 1 ）  2019年12月

    研究論文（学術雑誌）, 共著, 査読有り

    　概要を見る

    G protein-gated inwardly rectifying potassium channel (GIRK) plays a key role in regulating neurotransmission. GIRK is opened by the direct binding of the G protein βγ subunit (Gβγ), which is released from the heterotrimeric G protein (Gαβγ) upon the activation of G protein-coupled receptors (GPCRs). GIRK contributes to precise cellular responses by specifically and efficiently responding to the Gi/o-coupled GPCRs. However, the detailed mechanisms underlying this family-specific and efficient activation are largely unknown. Here, we investigate the structural mechanism underlying the Gi/o family-specific activation of GIRK, by combining cell-based BRET experiments and NMR analyses in a reconstituted membrane environment. We show that the interaction formed by the αA helix of Gαi/o mediates the formation of the Gαi/oβγ-GIRK complex, which is responsible for the family-specific activation of GIRK. We also present a model structure of the Gαi/oβγ-GIRK complex, which provides the molecular basis underlying the specific and efficient regulation of GIRK.

  • Nanodiscs for structural biology in a membranous environment

    Yokogawa M., Fukuda M., Osawa M.

    Chemical and Pharmaceutical Bulletin 67 （ 4 ） 321 - 326 2019年

    研究論文（学術雑誌）, 共著, 査読有り,  ISSN  00092363

    　概要を見る

    The structures of many membrane proteins have been analyzed in detergent micelles. However, the environment of detergent micelles differs somewhat from that of the lipid bilayer, where membrane proteins exhibit physiological functions. Therefore, a more membrane-like environment has been awaited for structural analysis of membrane proteins. Nanodiscs are “hockey-puck”-shaped lipid bilayer particles that distribute in a monodispersed manner in aqueous solution. We review how nanodiscs or protein-reconstituted nanodiscs are prepared and how they are utilized to analyze protein structure, dynamics, and interactions with lipid molecules using solution NMR and cryo-electron microscopy.

  • Structural basis for the ethanol action on G-protein-activated inwardly rectifying potassium channel 1 revealed by NMR spectroscopy.

    Toyama Y, Kano H, Mase Y,Yokogawa M, Osawa M, Shimada I

    Proc Natl Acad Sci U S A. 115 （ 15 ） 3858 - 3863 2018年03月

    研究論文（学術雑誌）, 共著, 査読有り,  ISSN  00278424

    　概要を見る

    Ethanol consumption leads to a wide range of pharmacological effects by acting on the signaling proteins in the human nervous system, such as ion channels. Despite its familiarity and biological importance, very little is known about the molecular mechanisms underlying the ethanol action, due to extremely weak binding affinity and the dynamic nature of the ethanol interaction. In this research, we focused on the primary in vivo target of ethanol, G-protein-activated inwardly rectifying potassium channel (GIRK), which is responsible for the ethanol-induced analgesia. By utilizing solution NMR spectroscopy, we characterized the changes in the structure and dynamics of GIRK induced by ethanol binding. We demonstrated here that ethanol binds to GIRK with an apparent dissociation constant of 1.0 M and that the actual physiological binding site of ethanol is located on the cavity formed between the neighboring cytoplasmic regions of the GIRK tetramer. From the methyl-based NMR relaxation analyses, we revealed that ethanol activates GIRK by shifting the conformational equilibrium processes, which are responsible for the gating of GIRK, to stabilize an open conformation of the cytoplasmic ion gate. We suggest that the dynamic molecular mechanism of the ethanol-induced activation of GIRK represents a general model of the ethanol action on signaling proteins in the human nervous system.

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総説・解説等 【 表示 ／ 非表示 】

  • Nuclear Magnetic Resonance Approaches for Characterizing Protein-Protein Interactions.

    Toyama Y, Mase Y, Kano H, Yokogawa Mariko, Osawa M, Shimada I

    Methods Mol Biol. 1684   115 - 128 2018年10月

    記事・総説・解説・論説等（学術雑誌）, 共著

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研究発表 【 表示 ／ 非表示 】

  • 14-3-3ζによる転写因子FOXO3aの阻害メカニズムの解明

    桑山知也，中塚将一，横川真梨子，河津光作，中村吏佐， 木村友美，田辺幹雄，千田俊哉，齋藤潤，佐谷秀行，大澤匡範

    第61回NMR討論会 (高知県立県民文化ホール（高知県高知市）) , 

    2022年11月
    , 

    ポスター発表

  • 新型コロナウイルスSARS-CoV-2スパイクタンパク質阻害剤の探索

    小林明日香、祝部真澄、山本雄一朗、村江真奈、清水芳実、酒井祥太、深澤征義、米澤朋起、清水祐吾、池田和由、横川真梨子、大澤匡範、野口耕司

    第34回微生物シンポジウム (オンライン) , 

    2022年08月
    , 

    口頭発表（一般）

  • COVID-19の原因となるタンパク質-タンパク質相互作用を標的とする合成中分子阻害剤のin silico解析

    米澤 朋起、清水 祐吾、池田 和由、山本 雄一朗、野口 耕司、酒井 祥太、深澤 征義、横川 真梨子、大澤 匡範

    日本薬学会第142回年会 (オンライン) , 

    2022年03月
    , 

    ポスター発表

  • リン酸化および14-3-3ζによる転写因子FOXO3aの阻害メカニズムの解明

    桑山知也, 中塚将一, 横川真梨子, 河津光作, 中村吏佐, 木村友美, 田辺幹雄, 齋藤潤, 千田俊哉, 佐谷秀行, 大澤匡範

    第44回日本分子生物学会年会, 

    2021年12月
    , 

    ポスター発表, 日本分子生物学会

  • B-cell translocation gene 2 (BTG2)によるポリA分解促進機構の解明

    石井裕一郎, 横川真梨子, 城えりか, 高嶋大翔, 沢崎綾一, 寒河江彪流, 尾上耕一, 星野真一, 大澤匡範

    第94回日本生化学大会年会, 

    2021年11月
    , 

    日本生化学会

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競争的研究費の研究課題 【 表示 ／ 非表示 】

  • B型肝炎ウイルスの肝細胞侵入・増殖機構の構造基盤と立体構造に基づく創薬

    2021年04月
    -
    2024年03月

    文部科学省・日本学術振興会, 科学研究費助成事業, 横川 真梨子, 基盤研究(C), 補助金,  研究代表者

  • B型肝炎ウイルスの肝細胞侵入および増殖機構の構造生物学的解析

    2018年04月
    -
    2021年03月

    文部科学省・日本学術振興会, 科学研究費助成事業, 横川　真梨子, 基盤研究(C), 補助金,  研究代表者

  • B型肝炎ウイルスの感染機構の構造基盤

    2016年04月
    -
    2018年03月

    文部科学省・日本学術振興会, 科学研究費助成事業, 横川　真梨子, 若手研究(B), 補助金,  研究代表者

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担当授業科目 【 表示 ／ 非表示 】

  • 課題研究（生命機能物理学）

    2022年度

  • 演習（生命機能物理学）

    2022年度

  • 卒業研究１（薬学科）

    2022年度

  • 高度研究機器特別演習

    2022年度

  • 物理化学３

    2022年度

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担当経験のある授業科目 【 表示 ／ 非表示 】

  • 薬学基礎実習

    慶應義塾

    2015年04月
    -
    2016年03月
    , 

    秋学期, 実習・実験

  • C1(4)物質の変化

    慶應義塾

    2015年04月
    -
    2016年03月
    , 

    秋学期, 講義

    反応速度

  • 薬学実習IIA（化学、物理）

    慶應義塾

    2015年04月
    -
    2016年03月
    , 

    春学期, 実習・実験

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