European Biophysics Journal

, Volume 47, Issue 4, pp 363–371 | Cite as

Immuno-receptors: from recognition to signaling and function

  • Israel Pecht


The vertebrate adaptive immune response is initiated by specific recognition of antigens. This is carried out by molecules, soluble or cell surface receptors that are members of the Multichain Immune Recognition Receptors (MIRR) group of proteins. The soluble arm of the response is based on antibodies. Kinetic analysis of antibody–antigenic epitope interactions pioneered insights into the complexity underlying the capacity of relatively limited repertoires of antibodies to recognize an essentially unlimited range of epitopes by employing conformational diversity of a given single sequence. The arm responsible for recognition of cellular targets involves a considerably more elaborate process, predominantly of antigen-derived peptides presented bound to molecules encoded by the major histocompatibility complex (MHC). This remarkable cellular recognition process performed by T-cell receptors requires earlier steps of peptide presentation and involves interactions of the receptor sites with the array of its MHC-peptide composite ligand. In both cases, antigen recognition needs to be followed by its coupling, by biochemical cascades, to different specific responses, namely activation of effector functions. The parameters required for coupling to functional responses are still a focus of intense research. In solution, antigen–antibody aggregation is one established activation process. Those required for coupling antigen recognition to cell activation, whether by Fc receptor bound antibodies or by the B-cell antigen receptor, are also still subject to active research efforts. Though activation by immune-receptors requires antigen recognition, considerable differences could exist among the requirements set by distinct cell types. Moreover, antigen binding requiring intercellular interactions introduces additional complexity.


Chemical relaxation Kinetics Antibody Antigenic epitope 


  1. Avalos AM, Bilate AM, Witte MD, Tai AK, He J, Frushicheva MP, Thill PD, Meyer-Wentrup F, Theile CS, Chakraborty AK, Zhuang X, Ploegh HL (2014) Monovalent engagement of the BCR activates ovalbumin-specific transnuclear B cells. J Exp Med 211:365–379CrossRefPubMedPubMedCentralGoogle Scholar
  2. Clegg RM, Loontiens FG, Jovin TM (1977) Binding of 4-methylumbelliferyl alpha-D-mannopyranoside to dimeric concanavalin A: fluorescence temperature-jump relaxation study. Biochemistry 16:167–175CrossRefPubMedGoogle Scholar
  3. Day LA, Sturtevant JM, Singer SJ (1963) The kinetics of the reactions between antibodies to the 2,4 dinitrophenyl group and specific haptens. Ann N Y Acad Sci 103:611–625CrossRefPubMedGoogle Scholar
  4. Diebolder CA, Beurskens FJ, de Jong RN, Koning RI, Strumane K, Lindorfer MA, Voorhorst M, Ugurlar D, Rosati S, Heck AJ, van de Winkel JG, Wilson IA, Koster AJ, Taylor RP, Saphire EO, Burton DR, Schuurman J, Gros P, Parren PW (2014) Complement is activated by IgG hexamers assembled at the cell surface. Science 343:1260–1263CrossRefPubMedPubMedCentralGoogle Scholar
  5. Fiala GJ, Schamel WWA, Blumenthal B (2011) Blue native polyacrylamide gel electrophoresis (BN-PAGE) for analysis of multiprotein complexes from cellular lysates. J Vis Exp.
  6. Fiala GJ, Kaschek D, Blumenthal B, Reth M, Timmer J, Schamel WW (2013) Pre-clustering of the B cell antigen receptor demonstrated by mathematically extended electron microscopy. Front Immunol 4:427CrossRefPubMedPubMedCentralGoogle Scholar
  7. Foote J, Milstein C (1991) Kinetic maturation of an immune response. Nature 352:530–532CrossRefPubMedGoogle Scholar
  8. Foote J, Milstein C (1994) Conformational isomerism and the diversity of antibodies. Proc Natl Acad Sci USA 22:10370–10374CrossRefGoogle Scholar
  9. Froese A, Sehon AH, Eigen M (1962) Kinetic studies of protein-dye and antibody–hapten interactions with the temperature-jump method. Can J Chem 40:1786–1797CrossRefGoogle Scholar
  10. Gakamsky DM, Lewitzki E, Grell E, Saulquin X, Malissen B, Montero-Julian F, Bonneville M, Pecht I (2007) Kinetic evidence for a ligand-binding-induced conformational transition in the T cell receptor. Proc Natl Acad Sci USA 104:16639–16644CrossRefPubMedPubMedCentralGoogle Scholar
  11. Givol D, Sharon J, Hochman J, Gavish M, Inbar D, Pecht I, Steinberg IZ, Schlessinger J (1977) Folding, association, and interactions of domains in the antibody molecule. Cold Spring Harb Symp Quant Biol 41(Pt 2):667–675CrossRefPubMedGoogle Scholar
  12. Haselkorn D, Friedman S, Givol D, Pecht I (1974) Kinetic mapping of the antibody combining site by chemical relaxation spectrometry. Biochemistry 13:2210CrossRefPubMedGoogle Scholar
  13. Huber R, Deisenhofer J, Colman P, Matsushima M, Palm W (1976) Crystallographic structure studies of an IgG molecule and an Fc fragment. Nature (London) 264:415–420CrossRefGoogle Scholar
  14. James LC, Roversi P, Tawfik DS (2003) Antibody multispecificity mediated by conformational diversity. Science 299:1362–1367CrossRefPubMedGoogle Scholar
  15. Jaton JC, Huser H, Braun DG, Givol D, Pecht I, Schlessinger J (1975) Conformational changes induced in a homogeneous anti-type III pneumococcal antibody by oligosaccharides of increasing size. Biochemistry 14(24):5312–5315CrossRefPubMedGoogle Scholar
  16. Klaesener K, Maity PC, Hobeika E, Yang J, Reth M (2014) B Cell activation involved nanoscale receptor reorganizations and inside-out signaling by Syk. eLife 3:e02069CrossRefGoogle Scholar
  17. Lancet D, Pecht I (1976) Kinetic evidence for a conformational transition induced in an immuno-globulin by hapten binding. Proc Natl Acad Sci USA 73:3549–3553CrossRefPubMedPubMedCentralGoogle Scholar
  18. Lee CH, Romain G, Yan W, Watanabe M, Charab W, Todorova B, Lee J, Triplett K, Donkor M, Lungu OI, Lux A, Marshall N, Lindorfer MA, Goff OR, Balbino B, Kang TH, Tanno H, Delidakis G, Alford C, Taylor RP, Nimmerjahn F, Varadarajan N, Bruhns P, Zhang YJ, Georgiou G (2017) IgG Fc domains that bind C1q but not effector Fcγ receptors delineate the importance of complement-mediated effector functions. Nat Immunol 8:889–898CrossRefGoogle Scholar
  19. Loontiens FG, Clegg RM, Van Landschoot A, Jovin TM (1977) Binding of 4-methylumbelliferyl alpha-D-mannopyranoside to tetrameric concanavalin A. Fluorescence temperature-jump relaxation study. Eur J Biochem 78:465–469CrossRefPubMedGoogle Scholar
  20. Maeda H, Schmidt-Kessen A, Engel J, Jaton JC (1977) Kinetic of Binding of oligosaccharides to a homogeneous pneumococcal antibody: dependence on antigen chain length suggests a labile-intermediate complex. Biochemistry 16:4086–4089CrossRefPubMedGoogle Scholar
  21. Manjula BN, Glaudemans CP, Mushinski EB, Potter M (1976) Subunit interactions in mouse myeloma proteins with anti-galactan activity. Proc Natl Acad Sci USA 73:932–936CrossRefPubMedPubMedCentralGoogle Scholar
  22. Morris AT, Lancet D, Pecht I, Givol D, Dwek RA (1980) N.M.R. investigation of hapten binding to the myeloma protein M-460. Int J Biol Macromol 2:39–44CrossRefGoogle Scholar
  23. Ortega E, Schweitzer-Stenner R, Pecht I (1988) Possible orientational constraints determine secretory signals induced by aggregation of IgE receptors on mast cells. EMBO J 7:4101–4109PubMedPubMedCentralCrossRefGoogle Scholar
  24. Pecht I (1976) Recognition and allostery in the mechanism of antibody action. In: Rajewski K, Melchers F (eds) The immune system. Springer, Heidelberg, pp 41–54CrossRefGoogle Scholar
  25. Pecht I (1982) Dynamic aspects of antibody function. In: Sela M (ed) The Antigens, vol VI. Academic Press, N.Y, pp 1–68Google Scholar
  26. Pecht I, Lancet D (1977) Chemical relaxation in molecular biology. Springer, New York, pp 307–336CrossRefGoogle Scholar
  27. Pecht I, Givol D, Sela M (1972a) Dynamics of hapten-antibody interaction. Studies on a Myeloma protein with anti-2, 4-dinitrophenyl specificity. J Mol Biol 68:241–247CrossRefPubMedGoogle Scholar
  28. Pecht I, Haselkorn D, Friedman S (1972b) Kinetic mapping of antibody binding sites by chemical relaxation spectroscopy. FEBS Lett 24:331–334CrossRefPubMedGoogle Scholar
  29. Pecht I, Ehrenberg B, Calef E, Arnon R (1977) Conformational changes and complement activation induced upon antigen binding to antibodies. Biochem Biophys Res Commun 74(4):1302–1310CrossRefPubMedGoogle Scholar
  30. Rao DN, Rudikoff S, Krutzsch H, Potter M (1979) Structural evidence for independent joining region gene in immunoglobulin heavy chains from anti-galactan myeloma proteins and its potential role in generating diversity in complementarity-determining regions. Proc Natl Acad Sci USA 76:2890–2894CrossRefPubMedPubMedCentralGoogle Scholar
  31. Rudikoff S, Rao DN, Glaudemans CP, Potter M (1980) kappa Chain joining segments and structural diversity of antibody combining sites. Proc Natl Acad Sci USA 77:4270–4274CrossRefPubMedPubMedCentralGoogle Scholar
  32. Schepers G, Blatt Y, Himmelspach K, Pecht I (1978) Binding site of a dextran-specific homogeneous IgM: thermodynamic and spectroscopic mapping by dansylated oligosaccharides. Biochemistry 17:2239–2245CrossRefPubMedGoogle Scholar
  33. Schlessinger J, Steinberg IZ, Givol D, Hochman J, Pecht I (1975) Antigen-induced conformational changes in antibodies and their Fab fragments studied by circular polarization of fluorescence. Proc Natl Acad Sci USA 72(7):2775–2779CrossRefPubMedPubMedCentralGoogle Scholar
  34. Schweitzer-Stenner R, Tamir I, Pecht I (1997) Analysis of Fc(epsilon)RI-mediated mast cell stimulation by surface-carried antigens. Biophys J 72:2470–2478CrossRefPubMedPubMedCentralGoogle Scholar
  35. Schweizer-Stenner R, Ortega E, Pecht I (1994) Kinetic of FcɛRI-dimer formation by specific monoclonal antibodies on mast cells. Biochemistry 33:8813–8825CrossRefGoogle Scholar
  36. Sela-Culang I, Alon S, Ofran Y (2012) A systematic comparison of free and bound antibodies reveals binding-related conformational changes. J Immunol 189(10):4890–4899CrossRefPubMedGoogle Scholar
  37. Sela-Culang I, Kunik V, Ofran Y (2013) The structural basis of antibody–antigen recognition. Front Immunol 4:302CrossRefPubMedPubMedCentralGoogle Scholar
  38. Sundberg EJ, Mariuzza RA (2003) Molecular recognition in antibody–antigen complexes. Adv Protein Chem 61:119–160CrossRefGoogle Scholar
  39. Tamir I, Schweitzer-Stenner R, Pecht I (1996) Immobilization of the type I receptor for IgE initiates signal transduction in mast cells. Biochemistry 35:6872–6883CrossRefPubMedGoogle Scholar
  40. Übelhart R, Hug E, Bach MP, Wossning T, Dühren-von Minden M, Horn AH, Tsiantoulas D, Kometani K, Kurosaki T, Binder CJ, Sticht H, Nitschke L, Reth M, Jumaa H (2015) Responsiveness of B cells is regulated by the hinge region of IgD. Nat Immunol 16:534–543CrossRefPubMedGoogle Scholar
  41. Volkmann C, Brings N, Becker M, Hobeika E, Yang J, Reth M (2016) Molecular requirements of the B-cell antigen receptor for sensing monovalent antigens. EMBO J 35:2371–2381CrossRefPubMedPubMedCentralGoogle Scholar
  42. Vuk-Pavlovic S, Blatt Y, Glaudemans CPJ, Lancet D, Pecht I (1978) Hapten-linked conformations equilibria in immunoglobulins XRPC-24 and J-539 observed by chemical relaxation. Biophys J 24:161–174CrossRefPubMedPubMedCentralGoogle Scholar
  43. Wedemayer GJ, Patten PA, Wang LH, Schultz PG, Stevens RC (1997) Structural insights into the evolution of an antibody combining site. Science 276:665–669CrossRefGoogle Scholar
  44. Wilson IA, Stanfield RL (1994) Antibody–antigen interactions: new structures and new conformational changes. Curr Opin Struct Biol 4:857–867 (Review)CrossRefPubMedGoogle Scholar
  45. Wilson BS, Oliver JM, Lidke DS (2011) Spatio-temporal signaling in mast cells. Adv Exp Med Biol 716:91–106CrossRefPubMedPubMedCentralGoogle Scholar
  46. Yang J, Reth M (2010a) The dissociation activation model of B cell antigen receptor triggering. FEBS Lett 584:4872–4877CrossRefPubMedGoogle Scholar
  47. Yang J, Reth M (2010b) Oligomeric organization of the B-cell antigen receptor on resting cells. Nature 467:465–469. CrossRefPubMedGoogle Scholar
  48. Zidovetzki R, Blatt Y, Glaudemans CPJ, Manjula BN, Pecht I (1980) A common mechanism of hapten binding to immunoglobulins and their heterologous chain recombinants. Biochemistry 19:2790–2795CrossRefPubMedGoogle Scholar

Copyright information

© European Biophysical Societies' Association 2018

Authors and Affiliations

  1. 1.Department of ImmunologyThe Weizmann Institute of ScienceRehovotIsrael

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