Nature 335, 188 - 190 (08 September 1988); doi:10.1038/335188a0

Elbow motion in the immunoglobulins involves a molecular ball-and-socket joint

Arthur M. Lesk^*† & Cyrus Chothia^*‡

^*MRC Laboratory of Molecular Biology, Hills Road, Cambridge CB2 2QH, UK
^†European Molecular Biology Laboratory, Meyerhofstrasse 1, Postfach 1022.09, D-6900 Heidelberg, FRG
^‡Christopher Ingold Laboratory, University College London, 20 Gordon Street, London WC1H 0AJ, UK

Studies by electron microscopy, fluorescence polarization, hydrodynamics and X-ray crystallography have demonstrated the ability of different parts of immunoglobulin molecules to move relative to each other. This movement facilitates the multiple interactions that antibodies make with polyvalent antigens and effector proteins. Comparisons of the atomic structures of immunoglobulins of the same sequence in different crystal environments, and of those with different sequences, have shown that the movements involve local changes in the conformation of the peptides linking different domains. These changes occur in (1) the hinge regions that link the Fab fragment to the Fc, and (2) the switch regions that link the V_L–V_H dimer to the C_L–C_H1 dimer^1–15. We show here that in immunoglobulins of known structure, the movement of the V_L–V_H dimer relative to the C_L–C_H1 dimer also involves the interactions of three V_H and two C_H1 residues that form the molecular equivalent of a ball-and-socket joint. The almost absolute conservation in the sequences of immunoglobulins and T-cell receptors of the residues that form these interactions suggests that this is a general feature of functional importance.

References

1.	Poljak, R. J., Amzel, L. M., Chen, B. L., Phizackerley, R. P. & Saul, F. Proc. natn. Acad. Sci. U.S.A. 71, 3440−3444 (1974). | ChemPort |
2.	Colman, P. M., Deisenhofer, J., Huber, R. & Palm, W. J. molec. Biol. 100, 257−282 (1976). | PubMed | ChemPort |
3.	Silverton, E. W., Navia, M. A. & Davis, D. R. Proc. natn. Acad. Sci. U.S.A. 74, 5140−5149 (1977). | ChemPort |
4.	Abola, E. E., Ely, K. R. & Edmundson, A. B. Biochemistry 19, 432−439 (1980). | Article | PubMed | ChemPort |
5.	Saul, F. A., Amzel, L. M. & Poljak, R. J. J. biol. Chem. 253, 585−597 (1978). | PubMed | ISI | ChemPort |
6.	Satow, Y., Cohen, G. H., Padlan, E. A. & Davies, D. R. J. molec. Biol. 190, 593−604 (1986). | Article | PubMed | ISI | ChemPort |
7.	Marquart, M., Deisenhofer, J. & Huber, R. J. molec. Biol. 141, 369−391 (1980). | Article | PubMed | ISI | ChemPort |
8.	Sun, S. E. et al. Proteins 1, 74−80 (1986). | Article | PubMed | ChemPort |
9.	Sheriff, S. et al. Proc. natn. Acad. Sci. U.S.A. 84, 8075−8079 (1987). | ChemPort |
10.	Amit, A. G., Mariuzza, R. A., Phillips, S. E. V. & Poljak, R. J. Science 233, 747−753 (1986). | PubMed | ISI | ChemPort |
11.	Colman, P. M. et al. Nature 326, 358−362 (1987). | Article | PubMed | ISI | ChemPort |
12.	Cygler, M., Boodhoo, A., Lee, J. S. & Anderson, W. F. J. biol. Chem. 262, 643−648 (1987). | PubMed | ChemPort |
13.	Prased, L., Vandonselaar, M., Lee, J. S. & Delbaere, L. T. J. J. biol. Chem. 263, 2571−2574 (1987).
14.	Vitali, J., Young, W. W., Schatz, V. B., Sobottka, S. E. & Kretsinger, R. H. J. molec. Biol. 198, 351−355 (1987). | PubMed | ChemPort |
15.	Davies, D. R. & Metzger, H. A. Rev. Immun. 1, 87−117 (1983). | Article | ISI | ChemPort |
16.	Bernstein, F. C. et al. J. molec. Biol. 112, 535−542 (1977). | PubMed | ChemPort |
17.	Rabat, E. A., Wu, T. T., Reid-Miller, M., Perry, H. M. & Gottesman, K. S. Sequences of Proteins of Immunological Interest 4th edn (Public Health Service, NIH, Washington DC, 1987).
18.	Chien, Y. et al. Nature 312, 31−35 (1984). | Article | PubMed | ISI | ChemPort |
19.	Hedrick, S. M., Nielsen, E. A., Kavaler, J., Cohen, D. I. & Davies, M. M. Nature 308, 153−158 (1984). | Article | PubMed | ISI | ChemPort |
20.	Saito, H. et al. Nature 312, 36−40 (1984). | Article | PubMed | ISI | ChemPort |
21.	Yanagi, Y. et al. Nature 308, 145−149 (1984). | Article | PubMed | ISI | ChemPort |
22.	Saito, H. et al. Nature 309, 757−762 (1984). | Article | PubMed | ISI | ChemPort |
23.	Chothia, C., Lesk, A. M., Dodson, G. G. & Hodgkin, D. C. Nature 302, 500−505 (1983). | Article | PubMed | ISI | ChemPort |
24.	Lesk, A. M. & Chothia, C. J. molec. Biol. 174, 175−191 (1984). | Article | PubMed | ChemPort |
25.	Elber, R. & Karplus, M. Science 235, 318−321 (1987). | PubMed | ISI | ChemPort |
26.	Perutz, M. F. Nature 228, 726−739 (1970). | Article | PubMed | ISI | ChemPort |
27.	Baldwin, J. & Chothia, C. J. molec. Biol. 129, 175−200 (1979). | Article | PubMed | ISI | ChemPort |
28.	Bennett, W. S. & Huber, R. Crit. Revs Biochem. 15, 291−384 (1984). | ChemPort |