Structural analyses of PMP22 and MPZ to reveal the molecular basis of Charcot-Marie-Tooth disease
| Project/Area Number |
18K06601
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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)
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| Project Period (FY) |
2018-04-01 – 2021-03-31
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| Project Status |
Completed (Fiscal Year 2020)
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| Budget Amount *help |
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2020: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2019: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2018: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
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| Keywords | シャルコー・マリー・トゥース病 / PMP22 / MPZ / ミエリン / 末梢神経 / シャコー・マリー・トゥース病 / NMR |
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| Outline of Final Research Achievements |
Myelin protein zero (MPZ) plays an essential role to stack lipid bilayers in peripheral myelin, and amino acid substitutions of the protein cause a neuropathy, Charcot-Marie-Tooth disease. To understand the molecular mechanism of the membrane adhesion by MPZ, we solved the crystal structure of the extracellular domain of human MPZ (hMPZ-ECD). In the crystal, hMPZ-ECD formed a doughnut-like 4mer, and the tetramer formed two types of 8mers; a stacked-doughnut-like (type 1) 8mer and an 8-shaped (type 2) 8mer. We analyzed the multimerization capability of the nanodiscs on which the hMPZ-ECD variants were immobilized. The hMPZ-ECD variant with the amino acid substitution at the type 2 inter-4mer interface induced the multimerization of the nanodiscs as the wild-type protein did, while the variant with the substitution at the type 1 interface did not induce the multimerization. These results suggested the type 1 interaction between the hMPZ-ECD-4mer is important for the membrane stacking.
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| Academic Significance and Societal Importance of the Research Achievements |
本研究において開発したナノミエリン法は、ミエリン特有の多重層膜構造を試験管中において再構成する新規解析手法であり、細胞を用いたミエリンの再構築手法と比較して簡便に、MPZ変異が多重層膜形成に及ぼす影響を評価することが可能である。本手法は、CMTDの病因解明のみならず、膜多重層形成に関与するタンパク質を標的とした薬物のスクリーニングなどに活用することが可能であり、医学・薬学的意義が存在する。
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Report
(4 results)
Research Products
(5 results)
