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Structural basis of assembly of the human T cell receptor–CD3 complex

Author

Listed:
  • De Dong

    (Harbin Institute of Technology)

  • Lvqin Zheng

    (Peking University
    Peking University)

  • Jianquan Lin

    (Harbin Institute of Technology)

  • Bailing Zhang

    (Harbin Institute of Technology)

  • Yuwei Zhu

    (Harbin Institute of Technology)

  • Ningning Li

    (Peking University)

  • Shuangyu Xie

    (Harbin Institute of Technology)

  • Yuhang Wang

    (Harbin Institute of Technology)

  • Ning Gao

    (Peking University)

  • Zhiwei Huang

    (Harbin Institute of Technology)

Abstract

The αβ T cell receptor (TCR), in association with the CD3γε–CD3δε–CD3ζζ signalling hexamer, is the primary determinant of T cell development and activation, and of immune responses to foreign antigens. The mechanism of assembly of the TCR–CD3 complex remains unknown. Here we report a cryo-electron microscopy structure of human TCRαβ in complex with the CD3 hexamer at 3.7 Å resolution. The structure contains the complete extracellular domains and all the transmembrane helices of TCR–CD3. The octameric TCR–CD3 complex is assembled with 1:1:1:1 stoichiometry of TCRαβ:CD3γε:CD3δε:CD3ζζ. Assembly of the extracellular domains of TCR–CD3 is mediated by the constant domains and connecting peptides of TCRαβ that pack against CD3γε–CD3δε, forming a trimer-like structure proximal to the plasma membrane. The transmembrane segment of the CD3 complex adopts a barrel-like structure formed by interaction of the two transmembrane helices of CD3ζζ with those of CD3γε and CD3δε. Insertion of the transmembrane helices of TCRαβ into the barrel-like structure via both hydrophobic and ionic interactions results in transmembrane assembly of the TCR–CD3 complex. Together, our data reveal the structural basis for TCR–CD3 complex assembly, providing clues to TCR triggering and a foundation for rational design of immunotherapies that target the complex.

Suggested Citation

  • De Dong & Lvqin Zheng & Jianquan Lin & Bailing Zhang & Yuwei Zhu & Ningning Li & Shuangyu Xie & Yuhang Wang & Ning Gao & Zhiwei Huang, 2019. "Structural basis of assembly of the human T cell receptor–CD3 complex," Nature, Nature, vol. 573(7775), pages 546-552, September.
  • Handle: RePEc:nat:nature:v:573:y:2019:i:7775:d:10.1038_s41586-019-1537-0
    DOI: 10.1038/s41586-019-1537-0
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    Cited by:

    1. Kei Saotome & Drew Dudgeon & Kiersten Colotti & Michael J. Moore & Jennifer Jones & Yi Zhou & Ashique Rafique & George D. Yancopoulos & Andrew J. Murphy & John C. Lin & William C. Olson & Matthew C. F, 2023. "Structural analysis of cancer-relevant TCR-CD3 and peptide-MHC complexes by cryoEM," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    2. Mathieu Ferrari & Matteo Righi & Vania Baldan & Patrycja Wawrzyniecka & Anna Bulek & Alexander Kinna & Biao Ma & Reyisa Bughda & Zulaikha Akbar & Saket Srivastava & Isaac Gannon & Mathew Robson & Jame, 2024. "Structure-guided engineering of immunotherapies targeting TRBC1 and TRBC2 in T cell malignancies," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    3. Nishant K. Singh & Jesus A. Alonso & Jason R. Devlin & Grant L. J. Keller & George I. Gray & Adarsh K. Chiranjivi & Sara G. Foote & Lauren M. Landau & Alyssa G. Arbuiso & Laura I. Weiss & Aaron M. Ros, 2022. "A class-mismatched TCR bypasses MHC restriction via an unorthodox but fully functional binding geometry," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    4. Hyun-Kyu Choi & Peiwen Cong & Chenghao Ge & Aswin Natarajan & Baoyu Liu & Yong Zhang & Kaitao Li & Muaz Nik Rushdi & Wei Chen & Jizhong Lou & Michelle Krogsgaard & Cheng Zhu, 2023. "Catch bond models may explain how force amplifies TCR signaling and antigen discrimination," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    5. Muaz Nik Rushdi & Victor Pan & Kaitao Li & Hyun-Kyu Choi & Stefano Travaglino & Jinsung Hong & Fletcher Griffitts & Pragati Agnihotri & Roy A. Mariuzza & Yonggang Ke & Cheng Zhu, 2022. "Cooperative binding of T cell receptor and CD4 to peptide-MHC enhances antigen sensitivity," Nature Communications, Nature, vol. 13(1), pages 1-16, December.

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