| Project/Area Number |
21K06988
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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 49040:Parasitology-related
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| Research Institution | Kobe University |
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Principal Investigator |
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| Project Period (FY) |
2021-04-01 – 2024-03-31
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| Project Status |
Completed (Fiscal Year 2023)
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| Budget Amount *help |
¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000)
Fiscal Year 2023: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2022: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
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| Keywords | トキソプラズマ / 寄生包膜 / Irgb6 / 結晶構造解析 / リン酸化 / 不活化 / X線結晶構造解析 / IRGB6 / GBP / クライオ電子顕微鏡解析 |
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| Outline of Research at the Start |
病原性原虫の寄生胞膜破壊機構を原子レベルで解明するために、トキソプラズマ寄生胞膜の破壊を先導するIRGB6とGBPの高分解能分子構造を構造生物学的手法（X線結晶構造解析とクライオ電子顕微鏡構造解析）によって解明し、得られた分子構造からIRGB6とGBPによる寄生胞破壊時の反応機構を明らかにする。その成果は、病原性原虫に対する宿主の感染防御機構の解明を推進するのみならず、新たな原虫感染阻害薬の開発に繋がるものである。
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| Outline of Final Research Achievements |
Irgb6 is recruited to and disrupts the PVM formed by Toxoplasma gondii. We have determined the crystal structures of the GTP-bound and nucleotide-free forms of mouse Irgb6. The membrane binding interface of Irgb6 has a unique conformation consisting of N- and C-terminal helical regions that form phospholipid binding sites. In silico phospholipid docking revealed the membrane-binding residues, which were validated by mutagenesis and cell-based assays. These data provide a new structural basis for Irgb6 recognition of T. gondii PVM.
We found that Thr95 of Irgb6 is phosphorylated in response to type II T. gondii infection and that the mutation disrupts its localisation to PVs. Structural analysis revealed that Irgb6-T95D leads to a conformational change in the G domain that allosterically alters the PV membrane-binding interface. In silico docking supported disruption of the PVM binding site. We provide new insights into the allosteric inactivation of Irgb6 induced by T. gondi.
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| Academic Significance and Societal Importance of the Research Achievements |
Irgb6がトキソプラズマ寄生胞膜を認識する機構と（おそらくトキソプラズマによって）Irgb6が不活化される機構を共に分子レベルで解明し、免疫系を理解する上で重要な新しい知見を得られた。これらの研究結果は、寄生虫感染症に対して生体に本来備わる防御機構をうまく利用した新たな治療法の開発につながるものと期待する。
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