Structure and function of IRGB6 and GBP, which lead the destruction of Toxoplasma gondii vacuole

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K06988
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 49040:Parasitology-related
• Research Institution: Kobe University
• Principal Investigator: Saijo-Hamano Yumiko (濱野由見子) 神戸大学, 医学研究科, 医学研究員 (00444513)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: トキソプラズマ / 寄生包膜 / Irgb6 / 結晶構造解析

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.

Free Research Field

構造生物学

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。