| Project/Area Number |
18K06078
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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 43020:Structural biochemistry-related
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| Research Institution | Tokyo Medical and Dental University |
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Principal Investigator |
Numoto Nobutaka 東京医科歯科大学, 難治疾患研究所, 助教 (20378582)
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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 |
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
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| Keywords | X線結晶構造解析 / 自己免疫疾患 / 核酸 / B細胞 / クライオ電子顕微鏡 / 単粒子解析 / シグナル伝達 |
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| Outline of Final Research Achievements |
The structural basis of the specific molecular recognition mechanism between the B cell inhibitory co-receptor CD72 and the self-antigen Sm/RNP has not been clarified. The purification method of the ligand binding domain of CD72 was improved to obtain a large amount of high-purity sample sufficient for crystallization. The crystal structure of the ligand-binding domain of CD72c, which is an allele associated with an autoimmune disease in mice, has been determined. The structure reveals that the electrostatic potential on the molecular surface was significantly different between normal CD72 and CD72c, and the negative charge patch of CD72c will cause the weaker binding affinity to Sm/RNP than that of normal CD72. In addition, structural analysis of the complex of CD72 and Sm/RNP by cryoEM was attempted. The preliminary results indicated that the samples are suitable for further structural determination.
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| Academic Significance and Societal Importance of the Research Achievements |
CD72が自己抗原であるSm/RNPを認識して結合し、自己抗体の産生を抑制する機構の解明は、疾患に関わる自己抗原への応答を特異的に阻害するしくみの存在をはじめて明らかにしたものである。CD72の機能を利用することで、自己免疫疾患に関わる核酸に対する免疫応答を選択的に制御するような、新しい概念に基づく治療法の確立につながる可能性が考えられる。CD72の機能を制御する分子の合理的な設計が可能となるよう、その構造生物学的基盤を提供する。
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