Structural basis of proteins related with innate immunity

2018 Fiscal Year Final Research Report

• Project/Area Number: 16H02494
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Structural biochemistry
• Research Institution: The University of Tokyo
• Principal Investigator: Shimizu Toshiyuki 東京大学, 大学院薬学系研究科(薬学部), 教授 (30273858)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Keywords: 自然免疫 / X線結晶構造解析 / Nod様受容体 / Toll様受容体

Outline of Final Research Achievements

Innate immunity serves as the first line of defense against invading pathogens such as bacteria and viruses, and active adaptive immunity. We focused on the innate immune proteins, and tried to reveal the ligand recognition and regulation mechanisms by structural studies.
We determined the crystal structure of rabbit NOD2 in an ADP-bound state. The structure reveals an inactive closed conformation. We found a hydrophobic pocket on the concave surface of the LRR domain, suitable for accommodating glycan or peptide moieties of MDP. Structural studies of TLR sensing a single-stranded nucleic acids (TLR7, 8, 9) revealed that these TLRs share common mechanism for activation mechanism. Roquin mediates mRNA degradation by recognizing the constitutive-decay element (CDE) followed by recruitment of the deadenylation machinery. Crystal structure of Roquin-RNA complex revealed that The CDE RNA, forming a stem-loop structure, bound to the positively charged surface of the ROQ domain.

Free Research Field

構造生物

Academic Significance and Societal Importance of the Research Achievements

NLRの構造は数例に限られており、NOD2の構造情報はNLRの活性化機構を解明するうえで重要な情報となる。一本鎖核酸を認識するTLRが有する共通性「リガンド結合部位が2ヶ所あり別々のリガンドが各部位に結合することにより協調的に活性化する」を解明したことは大きなインパクトを与えた。特にTLR7,8は低分子化合物によって活性化されることが知られており、立体構造情報はあらたな化合物開発に多大な貢献を示すと考えられる。