Atypical TNF-TNFR superfamily binding interface in the GITR-GITRL complex for T cell activation
Min Zhao,
Lijun Fu,
Yan Chai,
Meng Sun,
Yan Li,
Shuo Wang,
Jianxun Qi,
Bin Zeng,
Le Kang,
George F. Gao,
Shuguang Tan
Affiliations
Min Zhao
Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China; Beijing Institutes of Life Science, Chinese Academy of Sciences, Beijing 100101, China
Lijun Fu
Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China; College of Life Sciences, Jiangxi Science and Technology Normal University, Nanchang 330013, China
Yan Chai
Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China
Meng Sun
Beijing Institutes of Life Science, Chinese Academy of Sciences, Beijing 100101, China
Yan Li
Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China
Shuo Wang
Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China
Jianxun Qi
Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China
Bin Zeng
College of Life Sciences, Jiangxi Science and Technology Normal University, Nanchang 330013, China; College of Pharmacy, Shenzhen Technology University, Shenzhen 518118, China
Le Kang
Beijing Institutes of Life Science, Chinese Academy of Sciences, Beijing 100101, China
George F. Gao
Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China; Corresponding author
Shuguang Tan
Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China; Corresponding author
Summary: Glucocorticoid-induced tumor necrosis factor receptor family-related protein (GITR) is a critical regulatory molecule in modulation of T cell immune responses. Here we report the mouse GITR (mGITR) and mGITR ligand (mGITRL) complex structure and find that the binding interface of mGITR and mGITRL is distinct from the typical tumor necrosis factor superfamily (TNFSF)/TNF receptor superfamily (TNFRSF) members. mGITR binds to its ligand with a single domain, whereas the binding interface on mGITRL is located on the side, which is distal from conserved binding sites of TNFSF molecules. Mutational analysis reveals that the binding interface of GITR/GITRL in humans is conserved with that in the mouse. Substitution of key interacting D93-I94-V95 (DIV) in mGITR with the corresponding K93-F94-S95 (KFS) in human GITR enables cross-recognition with human GITRL and cross-activation of receptor signaling. The findings of this study substantially expand our understanding of the interaction of TNFSF/TNFRSF superfamily molecules and can benefit the future design of biologics by targeting GITR/GITRL.
