Binding stoichiometry of the cytotoxic T lymphocyte-associated molecule-4 (CTLA-4): A disulfide-linked homodimer binds two CD86 molecules

Peter S. Linsley, Steven G. Nadler, Jürgen Bajorath, Robert Peach, Helios T. Leung, Julie Rogers, Jeff Bradshaw, Mark Stebbins, Gina Leytze, William Brady, Alison R. Malacko, Hans Marquardt, Shyh Yu Shaw

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Abstract

CD28 and CTLA-4 are homologous T cell receptors of the immunoglobulin (Ig) superfamily, which bind B7 molecules (CD80 and CD86) on antigen-presenting cells and transmit important costimulatory signals during T cell activation. Here we have investigated the subunit structure of CTLA-4 and the stoichiometry of its binding to B7 molecules. We demonstrate CTLA-4 is a homodimer interconnected by one disulfide bond in the extracellular domain at cysteine residue 120. Each monomeric polypeptide chain of CTLA-4 contains a high affinity binding site for B7 molecules; soluble CTLA-4 and CD86 form complexes containing equimolar amounts of monomeric CTLA-4 and CD86 (i.e. a 2:2 molecular complex). Thus, CTLA-4 and probably CD28 have a receptor structure consisting of preexisting covalent homodimers with two binding sites. Dimerization of CTLA-4 and CD28 is not required for B7 binding, nor is it sufficient to trigger signaling.

Original languageEnglish
Pages (from-to)15417-15424
Number of pages8
JournalJournal of Biological Chemistry
Volume270
Issue number25
DOIs
Publication statusPublished - 1995 Jun 23

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Linsley, P. S., Nadler, S. G., Bajorath, J., Peach, R., Leung, H. T., Rogers, J., Bradshaw, J., Stebbins, M., Leytze, G., Brady, W., Malacko, A. R., Marquardt, H., & Shaw, S. Y. (1995). Binding stoichiometry of the cytotoxic T lymphocyte-associated molecule-4 (CTLA-4): A disulfide-linked homodimer binds two CD86 molecules. Journal of Biological Chemistry, 270(25), 15417-15424. https://doi.org/10.1074/jbc.270.25.15417