Lipid-dependent conformational dynamics underlie the functional versatility of T-cell receptor.
T-cell receptor-CD3 complex (TCR) is a versatile signaling machine that can initiate antigen-specific immune responses based on various biochemical changes of CD3 cytoplasmic domains, but the underlying structural basis remains elusive. Here we developed biophysical approaches to study the conformational dynamics of CD3ε cytoplasmic domain (CD3εCD). At the single-molecule level, we found that CD3εCDcould have multiple conformational states with different openness of three functional motifs, i.e., ITAM, BRS and PRS. These conformations were generated because different regions of CD3εCDhad heterogeneous lipid-binding properties and therefore had heterogeneous dynamics. Live-cell imaging experiments demonstrated that different antigen stimulations could stabilize CD3εCDat different conformations. Lipid-dependent conformational dynamics thus provide structural basis for the versatile signaling property of TCR.
State Key Laboratory of Molecular Biology, Shanghai Science Research Center, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences; University of Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China.
Xingdong
X
Guo
State Key Laboratory of Molecular Biology, Shanghai Science Research Center, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences; University of Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China.
Chengsong
C
Yan
State Key Laboratory of Molecular Biology, Shanghai Science Research Center, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences; University of Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China.
Hua
H
Li
Collaborative Innovation Center of Advanced Microstructures, National Laboratory of Solid State Microstructure and Department of Physics, Nanjing University, Nanjing, Jiangsu 210093, China.
Wenmao
W
Huang
State Key Laboratory of Molecular Biology, Shanghai Science Research Center, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences; University of Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China.
Xiaoshan
X
Shi
State Key Laboratory of Molecular Biology, Shanghai Science Research Center, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences; University of Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China.
Min
M
Huang
State Key Laboratory of Molecular Biology, Shanghai Science Research Center, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences; University of Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China.
Yingfang
Y
Wang
State Key Laboratory of Molecular Biology, Shanghai Science Research Center, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences; University of Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China.
Weiling
W
Pan
State Key Laboratory of Electroanalytical Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin 130022, China.
Mingjun
M
Cai
State Key Laboratory of Molecular Biology, Shanghai Science Research Center, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences; University of Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China.
Lunyi
L
Li
State Key Laboratory of Molecular Biology, Shanghai Science Research Center, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences; University of Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China.
Wei
W
Wu
State Key Laboratory of Molecular Biology, Shanghai Science Research Center, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences; University of Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China.
Yibing
Y
Bai
State Key Laboratory of Molecular Biology, Shanghai Science Research Center, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences; University of Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China.
Chi
C
Zhang
State Key Laboratory of Molecular Biology, Shanghai Science Research Center, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences; University of Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China.
Zhijun
Z
Liu
State Key Laboratory of Molecular Biology, Shanghai Science Research Center, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences; University of Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China.
Xinyan
X
Wang
Bioengineering Program & Department of Mechanical Engineering and Mechanics, Lehigh University, Bethlehem, PA 18015, USA.
Xiaohui F
XF
Zhang
State Key Laboratory of Magnetic Resonance and Atomic Molecular Physics, Wuhan Institute of Physics and Mathematics, Chinese Academy of Sciences, Wuhan, Hubei 430071, China.
Chun
C
Tang
State Key Laboratory of Electroanalytical Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin 130022, China.
Hongda
H
Wang
School of Life Sciences, Tsinghua University, Beijing 100084, China.
Wanli
W
Liu
State Key Laboratory of Molecular Biology, Shanghai Science Research Center, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences; University of Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China.
Bo
B
Ouyang
State Key Laboratory of Molecular Biology, Shanghai Science Research Center, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences; University of Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China.
Catherine C
CC
Wong
Collaborative Innovation Center of Advanced Microstructures, National Laboratory of Solid State Microstructure and Department of Physics, Nanjing University, Nanjing, Jiangsu 210093, China.
Yi
Y
Cao
State Key Laboratory of Molecular Biology, Shanghai Science Research Center, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences; University of Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China.|ShanghaiTech University, Shanghai 201210, China.
Chenqi
C
Xu
D000595:Amino Acid Sequence; D000941:Antigens / Q000378:metabolism; D001665:Binding Sites; D017252:CD3 Complex / Q000737:chemistry; D002470:Cell Survival; D006801:Humans; D007700:Kinetics; D008055:Lipids / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D008823:Micelles; D018625:Microscopy, Atomic Force; D011487:Protein Conformation; D011948:Receptors, Antigen, T-Cell / Q000737:chemistry* / Q000378:metabolism*; D012996:Solutions; D012997:Solvents / Q000737:chemistry; D020349:Surface Plasmon Resonance; D013601:T-Lymphocytes / Q000378:metabolism
D000941:Antigens; D017252:CD3 Complex; D008055:Lipids; D008823:Micelles; D011948:Receptors, Antigen, T-Cell; D012996:Solutions; D012997:Solvents