Crystal structure of a complete ternary complex of T-cell receptor, peptide-MHC, and CD4.

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TitleCrystal structure of a complete ternary complex of T-cell receptor, peptide-MHC, and CD4.
Publication TypeJournal Article
Year of Publication2012
AuthorsYin, Y, Wang, XXiang, Mariuzza, RA
JournalProc Natl Acad Sci U S A
Volume109
Issue14
Pagination5405-10
Date Published2012 Apr 3
ISSN1091-6490
KeywordsAntigens, CD4, Crystallography, X-Ray, Humans, Major Histocompatibility Complex, Models, Molecular, Molecular Structure, Peptides, Receptors, Antigen, T-Cell
Abstract

Adaptive immunity depends on specific recognition by a T-cell receptor (TCR) of an antigenic peptide bound to a major histocompatibility complex (pMHC) molecule on an antigen-presenting cell (APC). In addition, T-cell activation generally requires binding of this same pMHC to a CD4 or CD8 coreceptor. Here, we report the structure of a complete TCR-pMHC-CD4 ternary complex involving a human autoimmune TCR, a myelin-derived self-peptide bound to HLA-DR4, and CD4. The complex resembles a pointed arch in which TCR and CD4 are each tilted ∼65° relative to the T-cell membrane. By precluding direct contacts between TCR and CD4, the structure explains how TCR and CD4 on the T cell can simultaneously, yet independently, engage the same pMHC on the APC. The structure, in conjunction with previous mutagenesis data, places TCR-associated CD3εγ and CD3εδ subunits, which transmit activation signals to the T cell, inside the TCR-pMHC-CD4 arch, facing CD4. By establishing anchor points for TCR and CD4 on the T-cell membrane, the complex provides a basis for understanding how the CD4 coreceptor focuses TCR on MHC to guide TCR docking on pMHC during thymic T-cell selection.

DOI10.1073/pnas.1118801109
Alternate JournalProc. Natl. Acad. Sci. U.S.A.
PubMed ID22431638
PubMed Central IDPMC3325661
Grant ListAI036900 / AI / NIAID NIH HHS / United States
AI073654 / AI / NIAID NIH HHS / United States