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Structural basis for co-stimulation by the human CTLA-4/B7-2 complex.

Regulation of T-cell activity is dependent on antigen-independent co-stimulatory signals provided by the disulphide-linked homodimeric T-cell surface receptors, CD28 and CTLA-4 (ref. 1). Engagement of CD28 with B7-1 and B7-2 ligands on antigen-presenting cells (APCs) provides a stimulatory signal for T-cell activation, whereas subsequent engagement of CTLA-4 with these same ligands results in attenuation of the response. Given their central function in immune modulation, CTLA-4- and CD28-associated signalling pathways are primary therapeutic targets for preventing autoimmune disease, graft versus host disease, graft rejection and promoting tumour immunity. However, little is known about the cell-surface organization of these receptor/ligand complexes and the structural basis for signal transduction. Here we report the 3.2-A resolution structure of the complex between the disulphide-linked homodimer of human CTLA-4 and the receptor-binding domain of human B7-2. The unusual dimerization properties of both CTLA-4 and B7-2 place their respective ligand-binding sites distal to the dimer interface in each molecule and promote the formation of an alternating arrangement of bivalent CTLA-4 and B7-2 dimers that extends throughout the crystal. Direct observation of this CTLA-4/B7-2 network provides a model for the periodic organization of these molecules within the immunological synapse and suggests a distinct mechanism for signalling by dimeric cell-surface receptors.

Pubmed ID: 11279501


  • Schwartz JC
  • Zhang X
  • Fedorov AA
  • Nathenson SG
  • Almo SC



Publication Data

March 29, 2001

Associated Grants


Mesh Terms

  • Amino Acid Sequence
  • Antigens, CD
  • Antigens, CD86
  • Antigens, Differentiation
  • Binding Sites
  • CTLA-4 Antigen
  • Crystallography, X-Ray
  • Dimerization
  • Humans
  • Immunoconjugates
  • Lymphocyte Activation
  • Macromolecular Substances
  • Membrane Glycoproteins
  • Molecular Sequence Data
  • Protein Binding
  • Protein Conformation
  • Receptors, Antigen, T-Cell
  • Recombinant Proteins
  • Structure-Activity Relationship
  • T-Lymphocytes