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 】

  • 物理系薬学

  • 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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論文 【 表示 ／ 非表示 】

  • 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 （ 1 ） 3 2021年12月

    　概要を見る

    © 2021, The Author(s). 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 （Nature Communications)  10 （ 1 ）  2019年12月

    　概要を見る

    © 2019, The Author(s). 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 （Chemical and Pharmaceutical Bulletin)  67 （ 4 ） 321 - 326 2019年

    ISSN  00092363

    　概要を見る

    © 2019 The Pharmaceutical Society of Japan 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.

    Proceedings of the National Academy of Sciences of the United States of America （Proceedings of the National Academy of Sciences of the United States of America)  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

    © 2018 National Academy of Sciences. All rights reserved. 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.

  • Characterization of the multimeric structure of poly(A)-binding protein on a poly(A) tail

    Sawazaki R., Imai S., Yokogawa M., Hosoda N., Hoshino S., Mio M., Mio K., Shimada I., Osawa M.

    Scientific Reports （Scientific Reports)  8 （ 1 ） 1455 2018年01月

    研究論文（学術雑誌）, 査読有り

    　概要を見る

    © 2018 The Author(s). Eukaryotic mature mRNAs possess a poly adenylate tail (poly(A)), to which multiple molecules of poly(A)-binding protein C1 (PABPC1) bind. PABPC1 regulates translation and mRNA metabolism by binding to regulatory proteins. To understand functional mechanism of the regulatory proteins, it is necessary to reveal how multiple molecules of PABPC1 exist on poly(A). Here, we characterize the structure of the multiple molecules of PABPC1 on poly(A), by using transmission electron microscopy (TEM), chemical cross-linking, and NMR spectroscopy. The TEM images and chemical cross-linking results indicate that multiple PABPC1 molecules form a wormlike structure in the PABPC1-poly(A) complex, in which the PABPC1 molecules are linearly arrayed. NMR and cross-linking analyses indicate that PABPC1 forms a multimer by binding to the neighbouring PABPC1 molecules via interactions between the RNA recognition motif (RRM) 2 in one molecule and the middle portion of the linker region of another molecule. A PABPC1 mutant lacking the interaction site in the linker, which possesses an impaired ability to form the multimer, reduced the in vitro translation activity, suggesting the importance of PABPC1 multimer formation in the translation process. We therefore propose a model of the PABPC1 multimer that provides clues to comprehensively understand the regulation mechanism of mRNA translation.

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KOARA（リポジトリ）収録論文等 【 表示 ／ 非表示 】

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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

    総説・解説（学術雑誌）

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競争的資金等の研究課題 【 表示 ／ 非表示 】

  • 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,  代表

  • 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,  代表

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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）

    2020年度

  • 演習（生命機能物理学）

    2020年度

  • 卒業研究１（薬学科）

    2020年度

  • 物理化学３

    2020年度

  • 物理分析学

    2020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年度, 秋学期, 専門科目, 実習・実験

  • C1(4)物質の変化

    慶應義塾, 2015年度, 秋学期, 講義

    反応速度

  • 薬学実習IIA（化学、物理）

    慶應義塾, 2015年度, 春学期, 専門科目, 実習・実験

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