Structure of a fully assembled tumor-specific T cell receptor ligated by pMHC
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 electro...
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Published in | Cell Vol. 185; no. 17; pp. 3201 - 3213.e19 |
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Main Authors | , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
Elsevier Inc
18.08.2022
Cell Press |
Subjects | |
Online Access | Get full text |
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Summary: | 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 TCRαβ/CD3δγε2ζ2 complex bound to a melanoma-specific human class I pMHC at 3.08 Å resolution. The antigen-bound complex comprises 11 subunits stabilized by multivalent interactions across three structural layers, with clustered membrane-proximal cystines stabilizing the CD3-εδ and CD3-εγ 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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•Connecting peptides create rigid links to stabilize membrane-bound TCR subunits•Sterol lipid contributes to transmembrane assembly of the TCR complex•A pMHC/TCR structure highlights the cooperative nature of antigen recognition•TCR signaling may be triggered without spontaneous structural rearrangements
Cryo-EM structural analysis of a T cell receptor (TCR) complex bound to a tumor-specific human class I pMHC indicates the functional impact of connecting peptides and sterol lipid for complex assembly and suggests that TCR signaling may be triggered without spontaneous structural rearrangements. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 These authors contributed equally Lead contact |
ISSN: | 0092-8674 1097-4172 |
DOI: | 10.1016/j.cell.2022.07.010 |