2023 Fiscal Year Final Research Report
Structural analyses of PMP22 and MPZ to elucidate the molecular mechanism of Charcot-Marie-Tooth disease
| Project/Area Number |
21K06515
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Review Section |
Basic Section 47020:Pharmaceutical analytical chemistry and physicochemistry-related
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| Research Institution | Yokohama City University |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
三尾 和弘 国立研究開発法人産業技術総合研究所, 材料・化学領域, ラボチーム長 (40470041)
田辺 幹雄 大学共同利用機関法人高エネルギー加速器研究機構, 物質構造科学研究所, 特任准教授 (00716871)
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| Project Period (FY) |
2021-04-01 – 2024-03-31
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| Keywords | シャルコー・マリー・トゥース病 / ミエリンタンパク質ゼロ / MPZ / CMT1 / NMR |
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| Outline of Final Research Achievements |
Myelin protein zero (MPZ) is an essential protein to form peripheral myelin where it plays a role to form membrane layers by gluing membranes. Intermembrane adhesion is mediated by homophilic interactions between the extracellular domains (ECDs) of MPZ. Single amino acid substitutions in an ECD cause demyelinating neuropathy, Type 1 Charcot-Marie-Tooth disease (CMT1), with unknown mechanisms. In this study, by using an assay system named nanomyelin, we revealed that a CMT-related N87H substitution at the cis interface of the ECD 8-mer abolished the 8-mer-forming and membrane-adhesion activities. On the other hand, the CMT-related D32G and E68V substitutions did not affect membrane-stacking activity of ECD. However, the temperature-dependent changes in the CD signals of the ECD-variants revealed that the substitutions reduced the thermal stability of ECD. Reduced thermal stability may lead to impairment of the long-term stability of ECD and the layered membranes of myelin.
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| Free Research Field |
構造生物学
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| Academic Significance and Societal Importance of the Research Achievements |
本研究により、MPZのアミノ酸残基置換に起因するCMT1に対する創薬アプローチの指針が示された。N87H置換など、MPZ-ECDの多量体化・膜接着活性に対する異常を引き起こすバリアント群に対してはECD間相互作用部位を標的とした多量体化制御薬の探索が必要と考えられる。一方、E68V置換など、ECDの安定性・フォールディングの異常を引き起こすバリアント群に対しては薬理学的シャペロンのデザインが有効であると考えられる。
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