期刊
CELL
卷 185, 期 17, 页码 3201-+出版社
CELL PRESS
DOI: 10.1016/j.cell.2022.07.010
关键词
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资金
- Wellcome Trust [207547/Z/17/Z]
- European Research Council (ERC) [SFB 1507]
- DFG [57566863]
- Max Planck Society
- German Research Foundation [TA157/12-1]
- [789121]
- Wellcome Trust [207547/Z/17/Z] Funding Source: Wellcome Trust
This study reveals the structure of a tumor-reactive TCR complex bound to a melanoma-specific human class I pMHC, providing insights into the initiation of TCR signaling when the receptor binds to pMHC molecules.
The T cell receptor (TCR) expressed by T lymphocytes initiates protective immune responses to pathogens and tumors. To explore the structural basis of how TCR signaling is initiated when the receptor binds to peptide-loaded major histocompatibility complex (pMHC) molecules, we used cryogenic electron microscopy to determine the structure of a tumor-reactive TCR alpha beta/CD3 delta gamma epsilon(2)zeta(2) complex bound to a melanoma-specific human class I pMHC at 3.08 & Aring; resolution. The antigen-bound complex comprises 11 subunits stabilized by multivalent interactions across three structural layers, with clustered membrane-proximal cystines stabilizing the CD3-epsilon delta and CD3-epsilon gamma heterodimers. Extra density sandwiched between transmembrane helices reveals the involvement of sterol lipids in TCR assembly. The geometry of the pMHC/TCR complex suggests that efficient TCR scanning of pMHC requires accurate pre-positioning of T cell and antigen-presenting cell membranes. Comparisons of the ligand-bound and unliganded receptors, along with molecular dynamics simulations, indicate that TCRs can be triggered in the absence of spontaneous structural rearrangements.
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