Abstract
The failure to identify changes in the crystal structure of the T-cell antigen receptor (TCR) α/β ectodomains beyond the ligand-binding complementarity-determining region loops is most probably responsible for conformational changes having been relegated to a second plane as a mechanism of signal transduction. However, there is strong biochemical and spectroscopic evidence that the cytoplasmic tails of the tcr and the B-cell antigen receptor undergo conformational changes upon stimulation. This suggests that in the context of the whole TCR complex, including both the TCRα/β ectodomains and the complete CD3 subunits with their transmembrane and cytoplasmic tails, the conformational change has to be transmitted from the ectodomains to the cytoplasmic tails upon ligand binding. While the mechanism of transmission and the importance of conformational changes in T- and B-cell activation are still being elucidated, there are already functional correlates that establish a link between full T-cell activation and this conformational change.
This is a preview of subscription content, log in via an institution.
Buying options
Tax calculation will be finalised at checkout
Purchases are for personal use only
Learn about institutional subscriptionsPreview
Unable to display preview. Download preview PDF.
References
Wess J. G-protein-couplcd receptors: molecular mechanisms involved in receptor activation and selectivity of G-protein recognition. FASEB J 1997; 11:346–354.
Wess J, Liu J, Blin N et al. Structural basis of receptor/G protein coupling selectivity studied with muscarinic receptors as model systems. Life Sci 1997; 60:1007–1014.
Jiang G, Hunter T. Receptor signahng: when dimerization is not enough. Curr Biol 1999; 9:R568–571.
Banner DW, D’Arcy A, Janes W et al. Crystal structure of the soluble human 55 kd TNF receptor-himian TNF beta complex: implications for TNF receptor activation. Cell 1993; 73:431–445.
Chan FK, Chun HJ, Zheng L et al. A domain in TNF receptors that mediates ligand-independent receptor assembly and signaling. Science 2000; 288:2351–2354.
Chan FK, Siegel RM, Zacharias D et al. Fluorescence resonance energy transfer analysis of cell surface receptor interactions and signaling using spectral variants of the green fluorescent protein. Cytometry 2001; 44:361–368.
Krause CD, Mei E, Xie J et al. Seeing the light: Preassembly and ligand-induced changes of the interferon gamma receptor complex in cells. Mol Cell Proteomics 2002; 1:805–815.
Murali R, Cheng X, Berezov A et al. Disabling TNF receptor signaling by induced conformational perturbation of tryptophan-107. Proc Natl Acad Sci USA 2005; 102:10970–10975.
Remy I, Wilson IA, Michnick SW. Erythropoietin receptor activation by a ligand-induced conformation change Science 1999; 283:990–993.
Siegel RM, Frederiksen JK, Zacharias DA et al. Fas preassociation required for apoptosis signaling and dominant inhibition by pathogenic mutations. Science 2000; 288:2354–2357.
Walter MR, Windsor WT, Nagabhushan TL et al. Crystal structure of a complex between interferon-gamma and its soluble high-affinity receptor. Nature 1995; 376:230–235.
Rudolph MG, Stanfield RL, Wilson LA. How TCRs bind MHCs, peptides and coreceptors. Annu Rev Immunol 2006; 24:419–466.
Kjer-Nielsen L, Clements CS, Purcell AW et al. A Structural basis for the selection of dominant alphabeta T-cell receptors in antiviral immunity. Immunity 2003; 18:53–64.
Ding YH, Baker BM, Garboczi DN et al. Four A6-TCR/peptide/HLA-A2 structures that generate very different T-cell signals are nearly identical. Immunity 1999; 11:45–56.
Schamel WW, Arechaga I, Risueno RM et al. Coexistence of multivalent and monovalent TCRs explains high sensitivity and wide range of response. J Exp Med 2005; 202:493–503.
Minguet S, Swamy M, Alarcon B et al. Full activation of the T-cell receptor requires both clustering and conformational changes at CD3. Immunity 2007; 26:43–54.
Janeway CA Jr. Ligands for the T-cell receptor: Hard times for avidity models. Immunol Today 1995; 16:223–225.
Yoon ST, Dianzani U, Bottomly K et al. Both high and low avidity antibodies to the T-cell receptor can have agonist or antagonist activity. Immunity 1994; 1:563–569.
Aivazian D, Stern LJ. Phosphorylation of T-cell receptor zeta is regulated by a lipid dependent folding transition. Nat Struct Biol 2000; 7:1023–1026.
Laczko I, Hollosi M, Vass E et al. Conformational effect of phosphorylation on T-cell receptor/CD3 zeta-chain sequences. Biochem Biophys Res Commun 1998; 242:474–479.
Gil D, Schamel WW, Montoya M et al. Recruitment of Nek by CD3 epsilon reveals a ligand-induced conformational change essential for T-cell receptor signaling and synapse formation. Cell 2002; 109:901–912.
Gil D, Schrum AG, Alarcon B et al. T-cell receptor engagement by peptide-MHC ligands induces a conformational change in the CD3 complex of thymocytes. J Exp Med 2005; 201:517–522.
Risueno RM, Gil D, Fernandez E et al. Ligand-induced conformational change in the T-cell receptor associated with productive immune synapses. Blood 2005; 106:601–608.
Geisberger R, Crameri RA, chatz G. Models of signal transduction through the B-cell antigen receptor. Immunology. 2003; 110:401–410.
Cambier JC, Pleiman, CMClark, MR. Signal transduction by the B-cell antigen receptor and its coreceptors. Annu Rev Immunol 1994; 12:457–486.
Reth M. Hydrogen peroxide as second messenger in lymphocyte activation. Nat Immunol 2002; 3:1129–1134.
Tolar P, Sohn HW, Pierce SK. The initiation of antigen-induced B-cell antigen receptor signaling viewed in living cells by fluorescence resonance energy transfer. Nat Immunol 2005; 6:1168–1176.
Kato K, Fridman WH, Arata Y et al. A conformational change in the Fc precludes the binding of two Fcgamma receptor molecules to one IgG. Immunol Today 2000; 21:310–312.
Matsui K, Boniface JJ, Steffner P et al. Kinetics of T-cell receptor binding to peptide/I-Ek complexes: correlation of the dissociation rate with T-cell responsiveness. Proc Natl Acad Sci USA 1994; 91:12862–12866.
McKeithan, T W. Kinetic proofreading in T-cell receptor signal transduction. Proc Natl Acad Sci USA 1995; 92:5042–5046.
Davis MM, Boniface JJ, Reich Z et al. Ligand recognition by alpha beta T-cell receptors. Annu Rev Immunol 1998; 16:523–544.
Germain RN, Stefanova I. The dynamics of T-cell receptor signaling: complex orchestration and the key roles of tempo and cooperation. Annu Rev Immunol 1999; 17:467–522.
van der Merwe PA, Davis SJ. Molecular interactions mediating T-cell antigen recognition. Annu Rev Immunol 2003; 21:659–684.
Rudolph MG, Wilson IA. The specificity of TCR/pMHC interaction. Curr Opin Immunol 2002; 14:52–65.
van der Merwe PA. The TCR triggering puzzle. Immunity 2001; 14:665–668.
Qi S, Krogsgaard M, Davis MM et al. Molecular flexibility can influence the stimulatory ability of receptor-ligand interactions at cell-cell junctions. Proc Natl Acad Sci USA 2006; 103:4416–4421.
Krogsgaard M, Prado N, Adams EJ et al. Evidence that structural rearrangements and/or flexibility during TCR binding can contribute to T-cell activation. Mol Cell 2003; 12:1367–1378.
Schamel WW, Risueno RM, Minguet S et al. A conformation-and avidity-based proofreading mechanism for the TCR-CD3 complex. Trends Immunol 2006; 27:176–182.
Boniface JJ, Rabinowitz JD, Wulfing C et al. Initiation of signal transduction through the T-cell receptor requires the multivalent engagement of peptide/MHC ligands [corrected]. Immunity 1998; 9:459–466.
Cochran JR, Cameron TO, Stern LJ. The relationship of MHC-pcptide binding and T-cell activation probed using chemically defined MHC class II oligomers. Immunity 2000; 12:241–250.
Ottemann KM, Xiao W, Shin YK et al. A piston model for transmembrane signaling of the aspartate receptor. Science 1999; 285:1751–1754.
Burke CL, Stern DF. Activation of Neu (ErbB-2) mediated by disulfide bond-induced dimerization reveals a receptor tyrosine kinase dimer interface. Mol Cell Biol 1998; 18:5371–5379.
Misono KS, Ogawa H, Qiu Y et al. Structural studies of the natriuretic peptide receptor: A novel hormone-induced rotation mechanism for transmembrane signal transduction. Peptides 2005; 26:957–968.
Kubo Y, Tateyama M. Towards a view of functioning dimeric metabotropic receptors. Curr Opin Neurobiol 2005; 15:289–295.
Arnaout MA, Mahalingam B, Xiong JP. Integrin structure, allostery and bidirectional signaling. Annu Rev Cell Dev Biol 2005; 21:381–410.
Sun ZJ, Kim KS, Wagner G et al. Mechanisms contributing to T-cell receptor signaling and assembly revealed by the solution structure of an ectodomain fragment of the CD3 epsilon gamma heterodimer. CeU 2001; 105:913–923.
Kjer-Nielsen L, Dunstonc MA, Kostenko L et al. Crystal structure of the human T-cell receptor CD3 epsilon gamma heterodimer complexed to the therapeutic mAb OKT3. Proc Natl Acad Sci USA 2004; 101:7675–7680.
Kuhns MS, Davis MM, Garcia KC. Deconstructing the form and function of the TCR/CD3 complex. Immunity 2006; 24:133–139.
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2008 Landes Bioscience and Springer Science+Business Media
About this chapter
Cite this chapter
Risueño, R.M., Ortiz, A.R., Alarcón, B. (2008). Conformational Model. In: Sigalov, A.B. (eds) Multichain Immune Recognition Receptor Signaling. Advances in Experimental Medicine and Biology, vol 640. Springer, New York, NY. https://doi.org/10.1007/978-0-387-09789-3_10
Download citation
DOI: https://doi.org/10.1007/978-0-387-09789-3_10
Publisher Name: Springer, New York, NY
Print ISBN: 978-0-387-09788-6
Online ISBN: 978-0-387-09789-3
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)