title: Structure of murine CTLA-4 and its role in modulating T cell responsiveness.
abstract: The effective regulation of T cell responses is dependent on opposing signals transmitted through two related cell-surface receptors, CD28 and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4). Dimerization of CTLA-4 is required for the formation of high-avidity complexes with B7 ligands and for transmission of signals that attenuate T cell activation. We determined the crystal structure of the extracellular portion of CTLA-4 to 2.0 angstrom resolution. CTLA-4 belongs to the immunoglobulin superfamily and displays a strand topology similar to Valpha domains, with an unusual mode of dimerization that places the B7 binding sites distal to the dimerization interface. This organization allows each CTLA-4 dimer to bind two bivalent B7 molecules and suggests that a periodic arrangement of these components within the immunological synapse may contribute to the regulation of T cell responsiveness.
authors.affiliation: Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: D A
authors.initials: DA
authors.lastname: Ostrov
authors.forename: W
authors.initials: W
authors.lastname: Shi
authors.forename: J C
authors.initials: JC
authors.lastname: Schwartz
authors.forename: S C
authors.initials: SC
authors.lastname: Almo
authors.forename: S G
authors.initials: SG
authors.lastname: Nathenson
mesh_terms: D000069594:Abatacept; D000595:Amino Acid Sequence; D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000737:chemistry* / Q000276:immunology* / Q000378:metabolism; D018122:B7-1 Antigen / Q000737:chemistry / Q000378:metabolism; D018106:CD28 Antigens / Q000276:immunology / Q000378:metabolism; D060908:CTLA-4 Antigen; D018360:Crystallography, X-Ray; D019281:Dimerization; D006860:Hydrogen Bonding; D018796:Immunoconjugates; D008024:Ligands; D008213:Lymphocyte Activation; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011485:Protein Binding; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D015703:Antigens, CD; D000943:Antigens, Differentiation; D018122:B7-1 Antigen; D018106:CD28 Antigens; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D018796:Immunoconjugates; D008024:Ligands; D011948:Receptors, Antigen, T-Cell; D000069594:Abatacept