Li, Y. et al. Structure of a human autoimmune TCR bound to a myelin basic protein self-peptide and a multiple sclerosis-associated MHC class II molecule. EMBO J. 24, 2968-2979

Center for Advanced Research in Biotechnology, WM Keck Laboratory for Structural Biology, University of Maryland Biotechnology Institute, Rockville, MD 20850, USA.
The EMBO Journal (Impact Factor: 10.43). 10/2005; 24(17):2968-79. DOI: 10.1038/sj.emboj.7600771
Source: PubMed


Multiple sclerosis is mediated by T-cell responses to central nervous system antigens such as myelin basic protein (MBP). To investigate self-peptide/major histocompatibility complex (MHC) recognition and T-cell receptor (TCR) degeneracy, we determined the crystal structure, at 2.8 A resolution, of an autoimmune TCR (3A6) bound to an MBP self-peptide and the multiple sclerosis-associated MHC class II molecule, human leukocyte antigen (HLA)-DR2a. The complex reveals that 3A6 primarily recognizes the N-terminal portion of MBP, in contrast with antimicrobial and alloreactive TCRs, which focus on the peptide center. Moreover, this binding mode, which may be frequent among autoimmune TCRs, is compatible with a wide range of orientation angles of TCR to peptide/MHC. The interface is characterized by a scarcity of hydrogen bonds between TCR and peptide, and TCR-induced conformational changes in MBP/HLA-DR2a, which likely explain the low observed affinity. Degeneracy of 3A6, manifested by recognition of superagonist peptides bearing substitutions at nearly all TCR-contacting positions, results from the few specific interactions between 3A6 and MBP, allowing optimization of interface complementarity through variations in the peptide.

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    • "There are now several examples of autoreactive TCRs that bind to their MHCII + self peptides ligands at an unusual angle . Amongst these are two human TCRs , Ob . 1A12 and 3A6 , from the T cells of patients with multiple sclerosis that react with DRB1 * 1501 bound to a peptide included in MBP 85 – 101 ( Hahn et al . , 2005 ; Li et al . , 2005 ) . In both of these cases the TCR engages primarily the N - terminal end of the peptide and that portion of MHCII which surrounds that part of the peptide . Hence the TCR rotated is heavily tilted to - wards what is normally illustrated to be the left hand end of the MHC protein ( Fig . 2 ) . Recent work on TCRs , Ob . 2F3 and Ob . 3D1"
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    ABSTRACT: T cell recognition of foreign peptide antigen and tolerance to self peptides is key to the proper function of the immune system. Usually, in the thymus T cells that recognize self MHC + self peptides are deleted and those with the potential to recognize self MHC + foreign peptides are selected to mature. However there are exceptions to these rules. Autoimmunity and allergy are two of the most common immune diseases that can be related to recognition of self. Many genes work together to lead to autoimmunity. Of those, particular MHC alleles are the most strongly associated, reflecting the key importance of MHC presentation of self peptides in autoimmunity. T cells specific for combinations of self MHC and self peptides may escape thymus deletion, and thus be able to drive autoimmunity, for several reasons: the relevant self peptide may be presented at low abundance in the thymus but at high level in particular peripheral tissues; the relevant self peptide may bind to MHC in an unusual register, not present in the thymus but apparent elsewhere; finally the relevant self peptide may be post translationally modified in a tissue specific fashion. In some types of allergy, the peptide + MHC combination may also be fully derived from self. However the combination in question may be modified by the presence of other ligands, such as small drug molecules or metal ions. Thus these types of allergies may act like the post translationally modified peptides involved some types of autoimmunity.
    Protein & Cell 01/2013; 4(1):8-16. DOI:10.1007/s13238-012-2077-7 · 3.25 Impact Factor
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    • "The central role of the canonical docking polarity to the proper assembly of macromolecular signaling units predicts that any TCRs found to deviate from this polarity should signal poorly or not at all. Two autoreactive TCRs, specific for myelin basic protein (MBP)-derived peptides presented in the class II MHC HLA-DR2, that are presumed to have escaped negative selection by signaling poorly do deviate from the norm in their docking configurations (Hahn et al., 2005; Li et al., 2005). Both are unusual in that they are docked over the N-terminal half of the peptide, rather than the central portion of the peptide. "
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    ABSTRACT: "How does T cell receptor signaling begin?" Answering this question requires an understanding of how the parts of the molecular machinery that mediates this process fit and work together. Ultimately this molecular architecture must (i) trigger the relay of information from the TCR-pMHC interface to the signaling substrates of the CD3 molecules and (ii) bring the kinases that modify these substrates in close proximity to interact, initiate, and sustain signaling. In this contribution we will discuss advances of the last decade that have increased our understanding of the complex machinery and interactions that underlie this type of signaling.
    Frontiers in Immunology 06/2012; 3:159. DOI:10.3389/fimmu.2012.00159
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    • "TCR/pMHC complex structures have previously been solved by a number of different groups using individually determined crystallization conditions. In order to combine these data to generate a comprehensive TCR/pMHC Optimized Protein crystallization Screen (TOPS), we investigated the crystallization conditions of 16 previously published TCR/pMHC complexes (Garboczi et al., 1996; Garcia et al., 1996; Ding et al., 1998, 1999; Hennecke et al., 2000; Reiser et al., 2000, 2003; Hennecke and Wiley, 2002; Kjer-Nielsen et al., 2003; Stewart-Jones et al., 2003; Chen et al., 2005; Li et al., 2005; Maynard et al., 2005; Tynan et al., 2005, 2007; Sami et al., 2007; Cole et al., 2009) (Fig. 1). Although there was a substantial variation in the crystallization conditions identified for different TCR/pMHC complexes, we noticed certain trends. "
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    ABSTRACT: The interaction between the clonotypic αβ T cell receptor (TCR), expressed on the T cell surface, and peptide-major histocompatibility complex (pMHC) molecules, expressed on the target cell surface, governs T cell mediated autoimmunity and immunity against pathogens and cancer. Structural investigations of this interaction have been limited because of the challenges inherent in the production of good quality TCR/pMHC protein crystals. Here, we report the development of an 'intelligently designed' crystallization screen that reproducibly generates high quality TCR/pMHC complex crystals suitable for X-ray crystallographic studies, thereby reducing protein consumption. Over the last 2 years, we have implemented this screen to produce 32 T cell related protein structures at high resolution, substantially contributing to the current immune protein database. Protein crystallography, used to study this interaction, has already extended our understanding of the molecular rules that govern T cell immunity. Subsequently, these data may help to guide the intelligent design of T cell based therapies that target human diseases, underlining the importance of developing optimized approaches for crystallizing novel TCR/pMHC complexes.
    Journal of immunological methods 06/2012; 382(1-2):203-10. DOI:10.1016/j.jim.2012.06.007 · 1.82 Impact Factor
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