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A highly tilted binding mode by a self-reactive T cell receptor results in altered engagement of peptide and MHC.


ABSTRACT: Self-reactive T cells that escape elimination in the thymus can cause autoimmune pathology, and it is therefore important to understand the structural mechanisms of self-antigen recognition. We report the crystal structure of a T cell receptor (TCR) from a patient with relapsing-remitting multiple sclerosis that engages its self-peptide-major histocompatibility complex (pMHC) ligand in an unusual manner. The TCR is bound in a highly tilted orientation that prevents interaction of the TCR-? chain with the MHC class II ? chain helix. In this structure, only a single germline-encoded TCR loop engages the MHC protein, whereas in most other TCR-pMHC structures all four germline-encoded TCR loops bind to the MHC helices. The tilted binding mode also prevents peptide contacts by the short complementarity-determining region (CDR) 3? loop, and interactions that contribute to peptide side chain specificity are focused on the CDR3? loop. This structure is the first example in which only a single germline-encoded TCR loop contacts the MHC helices. Furthermore, the reduced interaction surface with the peptide may facilitate TCR cross-reactivity. The structural alterations in the trimolecular complex are distinct from previously characterized self-reactive TCRs, indicating that there are multiple unusual ways for self-reactive TCRs to bind their pMHC ligand.

SUBMITTER: Sethi DK 

PROVIDER: S-EPMC3023130 | biostudies-literature | 2011 Jan

REPOSITORIES: biostudies-literature

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A highly tilted binding mode by a self-reactive T cell receptor results in altered engagement of peptide and MHC.

Sethi Dhruv K DK   Schubert David A DA   Anders Anne-Kathrin AK   Heroux Annie A   Bonsor Daniel A DA   Thomas Chantz P CP   Sundberg Eric J EJ   Pyrdol Jason J   Wucherpfennig Kai W KW  

The Journal of experimental medicine 20110103 1


Self-reactive T cells that escape elimination in the thymus can cause autoimmune pathology, and it is therefore important to understand the structural mechanisms of self-antigen recognition. We report the crystal structure of a T cell receptor (TCR) from a patient with relapsing-remitting multiple sclerosis that engages its self-peptide-major histocompatibility complex (pMHC) ligand in an unusual manner. The TCR is bound in a highly tilted orientation that prevents interaction of the TCR-α chain  ...[more]

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