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Structure and Properties of Human Immunoglobulin Light-Chain Dimers

  • Fred J. Stevens
  • Marianne Schiffer
Part of the Methods In Molecular Medicine™ book series (MIMB, volume 51)

Abstract

Antibodies are multisubunit proteins, but unlike many other multisubunit proteins, it is possible to study structural and functional properties of an antibody subunit free of the others. Thus, antibodies are singular proteins in that they are highly amenable to analysis by a fundamental scientific research strategy, i.e., investigation of complex systems by study of its parts. The metabolism of even a superficially simple bacterial cell cannot be understood without a rigorous understanding of the kinetic properties of each of the enzymes involved. In much the same way, the quaternary interactions of protein subunits cannot be understood except in those relatively rare cases in which the subunit and individual domain components of a complex protein can be examined individually, yielding structural and biophysical information.

Keywords

Amyloid Fibril Variable Domain Immunoglobulin Superfamily Bence Jones Protein Amino Acid Insert 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

References

  1. 1.
    Stevens, F. J., Solomon, A., and Schiffer, M. (1991) Bence Jones proteins: a powerful tool for the fundamental study of protein chemistry and pathophysiology. Biochemistry 30, 6803–6805.PubMedCrossRefGoogle Scholar
  2. 2.
    Solomon, A. (1982) Bence Jones proteins: malignant or benign? New Engl. J. Med. 306, 605–607.PubMedCrossRefGoogle Scholar
  3. 3.
    Castano, E. and Frangione, B. (1988) Biology of disease: human amyloidosis, Alzheimer’s disease and related disorders. Lab. Invest. 58, 122–132.PubMedGoogle Scholar
  4. 4.
    Feiner, H. (1988) Pathology of dysproteinemia: light chain amyloidosis, non-amyloid immunoglobulin deposition disease, cryoglobulinemia syndromes, and macroglobulinemia of Waldenstrom. Human Pathol. 19, 1255–1272.CrossRefGoogle Scholar
  5. 5.
    Solomon, A. and Weiss, D. T. (1988) A perspective of plasma cell dyscrasias: clinical implications of monoclonal light chains in renal disease, in The Kidney in Plasma Cell Dyscrasias (Minetti, L., D’Amico, G., and Ponticelli, C., eds.), Kluwer Academic Publishers, Dordrecht, pp. 3–18.Google Scholar
  6. 6.
    Orfila, C., Leper, J.-C., Modesto, A., Bernadet, P., and Suc, J.-M. (1991) Fanconi’s syndrom, kappa light-chain myeloma, non-amyloid fibrils and cytoplasmic crystals in renal tubular epithelium. Am. J. Nephrol. 11, 345–349.PubMedCrossRefGoogle Scholar
  7. 7.
    Solomon, A. and Weiss, D. T. (1993) Ominous consequences of immunoglobulin deposition. New Engl. J. Med. 329, 1422–1423.PubMedCrossRefGoogle Scholar
  8. 8.
    Padlan, E. A. (1994) Anatomy of the antibody molecule. Mol Immunol. 31, 169–217.PubMedCrossRefGoogle Scholar
  9. 9.
    Fan, Z.-C., Shan, L., Guddat, L. W., He, Z.-M., Gray, W. R., Raison, R. L., and Edmundson, A. B. (1992) Three-dimensional structure of an Fv from a human IgM immunoglobulin. J. Mol. Biol. 228, 188–207.PubMedCrossRefGoogle Scholar
  10. 10.
    Chang, C.-H, Short, M. T., Westholm, F. A., Stevens, F. J., Wang, B.-C., Furey, W., Solomon, A., and Schiffer, M. (1985) Novel arrangement of immunoglobulin variable domains: X-ray crystallographic analysis of the lambda-chain dimer Bence Jones protein Loc. Biochemistry 24, 4890–4897.PubMedCrossRefGoogle Scholar
  11. 11.
    Schiffer, M., Ainsworth, C., Xu, Z.-B., Carperos, W., Olsen, K., Solomon, A., Stevens, F. J., and Chang, C.-H. (1989) Structure of a second crystal form of Bence Jones protein Loc: strikingly different domain associations in two crystal forms of a single protein. Biochemistry 28, 4066–4072.PubMedCrossRefGoogle Scholar
  12. 12.
    Furey, W., Wang, B. C., Yoo, C. S., and Sax, M. (1983) Structure of a novel Bence Jones protein (Rhe) fragment at 1.6 Å resolution. J. Mol. Biol. 167, 661–692.PubMedCrossRefGoogle Scholar
  13. 13.
    Xu, Z.-B. and Schiffer, M. (1988) The refinement and structure of Mcg Bence Jones dimer at 2.3 Å resolution. Ann. Mtg. Amer. Crystal. Assoc. PD28.Google Scholar
  14. 14.
    Ely, K. R., Herron, J. N., Harker, M., and Edmundson, A. B. (1989) Three-dimensional structure of a light chain dimer crystallized in water: conformational flexibility of a molecule in two crystal forms. J. Mol. Biol. 210, 601–615.PubMedCrossRefGoogle Scholar
  15. 15.
    Ely, K. R., Herron, J. N., and Edmundson, A. B. (1990) Three-dimensional structure of a hybrid light chain dimer: protein engineering of a binding cavity. Mol. Immunol. 27, 101–114.PubMedCrossRefGoogle Scholar
  16. 16.
    Fehlhammer H., Schiffer, M., Epp, O., Colman, P. M., Lattman, E. E., Schwager, P., Steigemann, W. S., and Schramm, H. J. (1975) The structure determination of the variable portion of the Bence Jones protein Au. Biophys. Struct. Mechanism 1, 139–146.CrossRefGoogle Scholar
  17. 17.
    Epp, O., Lattman, E., Schiffer, M., Huber, R., and Palm, W. (1975) The molecular structure of a dimer composed of the variable portions of the Bence Jones protein Rei refined at 2.0 Å resolution. Biochemistry 14, 4943–4952.PubMedCrossRefGoogle Scholar
  18. 18.
    Colman, P., Schramm, H., and Guss, J. (1977) Crystal and molecular structure of the dimer of variable domains of the Bence Jones protein Roy. J. Mol. Biol. 116, 73–79.PubMedCrossRefGoogle Scholar
  19. 19.
    Schiffer, M., Girling, R., Ely, K. R., and Edmundson, A. B. (1973) Structure of a lambda-type Bence Jones protein at 3.5 Å resolution. Biochemistry 12, 4620–4631.PubMedCrossRefGoogle Scholar
  20. 20.
    Poljak, R. J., Amzel, L. M., Avey, H. P., Chen, B. L., Phizackerley, R. P., and Saul, F. (1973) Three-dimensional structure of the Fab′ fragment of a human immunoglobulin at 2.8 Å resolution. Proc. Natl. Acad. Sci. USA 70, 3305–3310.PubMedCrossRefGoogle Scholar
  21. 21.
    Segal, D. M., Padlan, E. A., Cohen, G. H., Rudikoff, S., Potter, M., and Davies, D. R. (1974) The three-dimensional structure of a phosphorylcholine-binding mouse immunoglobulin Fab and the nature of the antigen binding site. Proc. Natl. Acad. Sci. USA 71, 4298–4302.PubMedCrossRefGoogle Scholar
  22. 22.
    Wu, T. T. and Kabat, E. A. (1972) An analysis of the sequences of the variable regions of Bence Jones proteins and myeloma light chains and their implications for antibody complementarity. J. Exp. Med. 132, 211–250.CrossRefGoogle Scholar
  23. 23.
    Edmundson, A. B., Ely, K. R., Abola, E. E., Schiffer, M., and Panagiotopoulos, N. (1975) Rotational allomerism and divergent evolution of domains in immunoglobulin light chains. Biochemistry 14, 3953–3961.CrossRefGoogle Scholar
  24. 24.
    Schiffer, M., Stevens, F. J., Westholm, F. A., Carlson, D., and Schoenborn, B. (1982) Small angle neutron scattering study of Bence Jones protein Mcg: comparison of structures in solution and in crystal. Biochemistry 21, 2874–2878.PubMedCrossRefGoogle Scholar
  25. 25.
    Schiffer, M., Westholm, F. A., Panagiotopoulos, N., and Solomon, A. (1978) Crystallographic data on a complete κ-type human Bence Jones protein. J. Mol. Biol 124, 287–290.PubMedCrossRefGoogle Scholar
  26. 25a.
    Huang, D.-B., Chang, C.-H., Ainsworth, C., Brunger, A. T., Eulite, M., Solomon, A., Stevens, F. J., Schiffer, M. (1994) Comparison of crystal structures of two homologous proteins: structural origin of altered domain interactions in immunoglobulin light-chain dimers. Biochemistry 33, 14,848–14,857.PubMedCrossRefGoogle Scholar
  27. 26.
    Klein, R., Jaenichen, R., and Zachau, H. G. (1993) Expressed human immunoglobulin κ genes and their hypermutation. Eur. J. Immunol. 23, 3248–3271.PubMedCrossRefGoogle Scholar
  28. 27.
    Rocca, A., Khamlichi, A. A., Aucouturier, P., Noel, L.-H., Denoryoy, L., and Preud’homme, J. L. (1993) Primary structure of a variable region of the VkI subgroup (ISE) in light chain deposition disease. Clin. Exp. Immunol. 91, 506–509.PubMedCrossRefGoogle Scholar
  29. 28.
    Cogne, M., Preud’homme, J.-L, Bauwens, M., Touchard, G., and Aucouturier, P. (1991) Structure of a monoclonal kappa chain of the V-kappa-IV subgroup in the kidney and plasma cells in light chain deposition disease. J. Clin Invest. 87, 2188–2190.CrossRefGoogle Scholar
  30. 29.
    Liepnieks, J. J., Dwulet, F. E., and Benson, M. D. (1990) Amino acid sequence of a kappa I primary (AL) amyloid protein (AND). Mol. Immunol. 27, 481–485.PubMedCrossRefGoogle Scholar
  31. 30.
    Hurle, M. R., Helms, L., Li, L., Chan, W., and Wetzel, R. (1994) A role for destabilizing amino acid replacements in light chain amyloidosis. Proc. Natl. Acad. Sci. USA 91, 5446–5450.PubMedCrossRefGoogle Scholar
  32. 31.
    Ch’ang, L.-Y., Yen, C.-P., Besl, L., Schell, M., and Solomon, A. (1994) Identification and characterization of a functional human IgλVI germline gene. Mol. Immunol. 31, 531–536.CrossRefGoogle Scholar
  33. 32.
    Reidl, L. S., Kinoshita, C. M., and Steiner, L. A. (1992) Wild mice express an Ig V-lambda gene that differs from any V-lambda in BALB/c but resembles a human V-lambda subgroup. J. Immunol. 149, 471–480.PubMedGoogle Scholar
  34. 33.
    Chuchana, P., Blancher, A., Brockly, F., Alexandre, D., Leranc, G., and Lefranc, M.-P. (1989) Definition of the human immunoglobulin variable lambda (IGLV) gene subgroups. Eur. J. Immunol. 20, 1317–1325.CrossRefGoogle Scholar
  35. 34.
    Edelman, G. M. and Gally, J. A. (1962) The nature of Bence Jones proteins: chemical similarities to polypeptide chains of myeloma globulins and normal gamma-globulins. J. Exp. Med. 116, 207–227.PubMedCrossRefGoogle Scholar
  36. 35.
    Green, R. W. (1973) Conformation and association of the light chain from a homogeneous human immunoglobulin. Biochemistry 12, 3225–3231.PubMedCrossRefGoogle Scholar
  37. 36.
    Azuma, T., Hamaguchi, K., and Migita, S. (1974) Interactions between immunoglobulin polypeptide chains. J. Biochem. 76, 685–693.PubMedGoogle Scholar
  38. 37.
    Maeda, H., Engel, J., and Schramm, H. J. (1976) Kinetics of dimerization of the variable fragment of the Bence Jones protein Au. Eur. J. Biochem. 69, 133–139.PubMedCrossRefGoogle Scholar
  39. 38.
    Stevens, F. Westholm, J., F., Solomon, A., and Schiffer, M. (1980) Self-association of human immunoglobulin κI light chains: role of the third hypervariable region. Proc. Natl. Acad. Sci USA 77, 1144–1148.PubMedCrossRefGoogle Scholar
  40. 39.
    Stevens, F. J. and Schiffer, M. (1981) Computer simulation of protein self-association during small-zone gel filtration: estimation of equilibrium constants. Biochem. J. 195, 213–219.PubMedGoogle Scholar
  41. 40.
    Kolmar, H., Frisch, C., Kleemann, G., Gotze, K., Stevens, F. J., and Fritz, H.-J. (1994) Dimerization of Bence Jones proteins: linking the rate of transcription from an Escherichia coli promoter to the association constant of REIv. Biol. Chem. Hoppe-Seyler 375, 61–70.PubMedCrossRefGoogle Scholar
  42. 41.
    Dorrington, K. J. (1978) The structural basis for the functional versatility of immunoglobulin G. Can. J. Biochem. 56, 1087–1101.PubMedCrossRefGoogle Scholar
  43. 42.
    Schiffer, M., Chang, C.-H., Naik, V. M., and Stevens, F. J. (1988) Analysis of immunoglobulin domain interactions: evidence for a dominant role of salt bridges. J. Mol. Biol. 203, 799–802.PubMedCrossRefGoogle Scholar
  44. 43.
    Jones, H. B. (1848) On a new substance occurring in the urine of a patient with mollities ossium. Phil. Trans. R. Soc. Lond. 55–62.Google Scholar
  45. 44.
    Neet, K. and Putnam, F. W. (1966) Characterization of the thermal denaturation of Bence Jones proteins by ultracentrifugation at elevated temperatures. J. Biol Chem. 241, 2320–2325.PubMedGoogle Scholar
  46. 45.
    Stone, M. J. (1990) Amyloidosis: a final common pathway for protein deposition in tissues. Blood 75, 531–545.PubMedGoogle Scholar
  47. 46.
    Myatt E., Westholm, F. A., Weiss, D. T., Solomon, A., Schiffer, M., and Stevens, F. J. (1994) Pathogenic potential of human monoclonal immunoglobulin light chains: relationship of in vitro aggregation to in vivo organ deposition. Proc. Natl. Acad. Sci. USA 91, 3034–3038.PubMedCrossRefGoogle Scholar
  48. 47.
    Solomon, A., Weiss, D. T., and Kattine, A. (1991) Nephropathological potential of human Bence Jones proteins: experimental and clinical correlates. N. Engl. J. Med. 324, 1845–1851.PubMedCrossRefGoogle Scholar
  49. 48.
    Abrahamson, M. and Grubb, A. (1994) Increased body temperature accelerates aggregation of the Leu-68 Gln mutant cystatin C, the amyloid-forming protein in hereditary cystatin C amyloid angiopathy. Proc. Natl. Acad. Sci. USA 91, 1416–1420.PubMedCrossRefGoogle Scholar
  50. 49.
    Stevens, F. J., Chang, C.-H., and Schiffer, M. (1988) Dual conformations of an immunogloublin light-chain dimer: heterogeneity of antigen specificity and idiotope profile may result from multiple variable-domain interaction mechanisms. Proc. Natl. Acad. Sci. USA 85, 6895–6899.PubMedCrossRefGoogle Scholar
  51. 49a.
    Foote, J. and Molstein, C. (1994) Conformational isomerism and the diversity of antibodies. Proc. Natl. Acad Sci. USA 91, 10,370–10,374.PubMedCrossRefGoogle Scholar
  52. 50.
    Jones, P. T., Dear, P. H., Foote, J., Neuberger, M. S., and Winter, G. (1986) Replacing the complementarity-determining regions in a human antibody with those from a mouse. Nature 321, 522–525.PubMedCrossRefGoogle Scholar
  53. 51.
    Riechmann, L., Clark, M., Waldmann, H., and Winter, G. (1988) Reshaping human antibodies for therapy. Nature 332, 323–327.PubMedCrossRefGoogle Scholar
  54. 52.
    Foote, J. and Winter, G. (1992) Antibody framework residues affecting the conformation of the hypervariable loops. J. Mol. Biol. 224, 487–499.PubMedCrossRefGoogle Scholar
  55. 53.
    Kabat, E. A., Wu, T. T., Perry, H. M., Gottesman, K. S., and Foeller, C. (1991) Sequences of Proteins of Immunological Interest, 5th ed., Public Health Service National Institutes of Health, Washington, DC.Google Scholar

Copyright information

© Humana Press Inc. 1995

Authors and Affiliations

  • Fred J. Stevens
    • 1
  • Marianne Schiffer
    • 1
  1. 1.Center for Mechanistic Biology and BiotechnologyArgonne National LaboratoryArgonne

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