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.
[1] Department of Microbiology and Immunology, [2] These authors contributed equally to this work.
J C
JC
Schwartz
X
X
Zhang
A A
AA
Fedorov
S G
SG
Nathenson
S C
SC
Almo
D000069594:Abatacept; D000595:Amino Acid Sequence; D015703:Antigens, CD / Q000737:chemistry* / Q000502:physiology; D000943:Antigens, Differentiation / Q000737:chemistry* / Q000502:physiology; D051940:B7-2 Antigen; D001665:Binding Sites; D060908:CTLA-4 Antigen; D018360:Crystallography, X-Ray; D019281:Dimerization; D006801:Humans; D018796:Immunoconjugates; D008213:Lymphocyte Activation; D046911:Macromolecular Substances; D008562:Membrane Glycoproteins / Q000737:chemistry* / Q000502:physiology; D008969:Molecular Sequence Data; D011485:Protein Binding; D011487:Protein Conformation; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry; D013329:Structure-Activity Relationship; D013601:T-Lymphocytes / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism
D015703:Antigens, CD; D000943:Antigens, Differentiation; D051940:B7-2 Antigen; C497964:CD86 protein, human; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D018796:Immunoconjugates; D046911:Macromolecular Substances; D008562:Membrane Glycoproteins; D011948:Receptors, Antigen, T-Cell; D011994:Recombinant Proteins; D000069594:Abatacept