Structural Basis of Plasticity in T Cell Receptor Recognition of a Self Peptide-MHC Antigen

The T cell receptor (TCR) inherently has dual specificity. T cells must recognize self-antigens in the thymus during maturation and then discriminate between foreign pathogens in the periphery. A molecular basis for this cross-reactivity is elucidated by the crystal structure of the alloreactive 2C...

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Bibliographic Details
Published in:	Science (American Association for the Advancement of Science) Vol. 279; no. 5354; pp. 1166 - 1172
Main Authors:	Garia, K. Christopher, Degano, Massimo, Pease, Larry R., Huang, Mingdong, Peterson, Per A., Teyton, Luc, Wilson, Ian A.
Format:	Journal Article
Language:	English
Published:	Washington, DC American Society for the Advancement of Science 20-02-1998 American Association for the Advancement of Science The American Association for the Advancement of Science
Subjects:	Animals Antigen receptors, T cell Antigens Binding sites Biological and medical sciences Cellular biology Crystal structure Crystallization Crystallography, X-Ray Crystals Fundamental and applied biological sciences. Psychology Fundamental immunology H-2 Antigens - chemistry H-2 Antigens - immunology H-2 Antigens - metabolism Immune recognition Immunobiology Ligands Lymphoid cells: ontogeny, maturation, markers, receptors, circulation and recirculation Mice Mice, Transgenic Models, Molecular Molecules Mutation Oligopeptides - chemistry Oligopeptides - immunology Oligopeptides - metabolism Peptides Physiological aspects Protein Conformation Protein Structure, Secondary Receptors Receptors, Antigen, T-Cell, alpha-beta - chemistry Receptors, Antigen, T-Cell, alpha-beta - immunology Receptors, Antigen, T-Cell, alpha-beta - metabolism Recombinant Proteins Scientific Concepts Surface areas T cell antigen receptors T cells T lymphocytes Topology Antigen Cellular immunity Self non self recognition T cell receptor Histocompatibility restriction Major histocompatibility system
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Summary:	The T cell receptor (TCR) inherently has dual specificity. T cells must recognize self-antigens in the thymus during maturation and then discriminate between foreign pathogens in the periphery. A molecular basis for this cross-reactivity is elucidated by the crystal structure of the alloreactive 2C TCR bound to self peptide-major histocompatibility complex (pMHC) antigen H-2K$^b$-dEV8 refined against anisotropic 3.0 angstrom resolution x-ray data. The interface between peptide and TCR exhibits extremely poor shape complementarity, and the TCR β chain complementarity-determining region 3 (CDR3) has minimal interaction with the dEV8 peptide. Large conformational changes in three of the TCR CDR loops are induced upon binding, providing a mechanism of structural plasticity to accommodate a variety of different peptide antigens. Extensive TCR interaction with the pMHC α helices suggests a generalized orientation that is mediated by the V$_\alpha$ domain of the TCR and rationalizes how TCRs can effectively "scan" different peptides bound within a large, low-affinity MHC structural framework for those that provide the slight additional kinetic stabilization required for signaling.
Bibliography:	ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 ObjectType-Article-1 ObjectType-Feature-2
ISSN:	0036-8075 1095-9203
DOI:	10.1126/science.279.5354.1166