title: Crystal structure of a soluble CD28-Fab complex.
abstract: Naive T cell activation requires signaling by the T cell receptor and by nonclonotypic cell surface receptors. The most important costimulatory protein is the monovalent homodimer CD28, which interacts with CD80 and CD86 expressed on antigen-presenting cells. Here we present the crystal structure of a soluble form of CD28 in complex with the Fab fragment of a mitogenic antibody. Structural comparisons redefine the evolutionary relationships of CD28-related proteins, antigen receptors and adhesion molecules and account for the distinct ligand-binding and stoichiometric properties of CD28 and the related, inhibitory homodimer CTLA-4. Cryo-electron microscopy-based comparisons of complexes of CD28 with mitogenic and nonmitogenic antibodies place new constraints on models of antibody-induced receptor triggering. This work completes the initial structural characterization of the CD28-CTLA-4-CD80-CD86 signaling system.
authors.affiliation: Nuffield Department of Clinical Medicine, The University of Oxford, John Radcliffe Hospital, Headington, Oxford, OX3 9DU, UK.
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Evans
authors.forename: Robert M
authors.initials: RM
authors.lastname: Esnouf
authors.forename: Raquel
authors.initials: R
authors.lastname: Manso-Sancho
authors.forename: Robert J C
authors.initials: RJ
authors.lastname: Gilbert
authors.forename: John R
authors.initials: JR
authors.lastname: James
authors.forename: Chao
authors.initials: C
authors.lastname: Yu
authors.forename: Janet A
authors.initials: JA
authors.lastname: Fennelly
authors.forename: Cheryl
authors.initials: C
authors.lastname: Vowles
authors.forename: Thomas
authors.initials: T
authors.lastname: Hanke
authors.forename: Björn
authors.initials: B
authors.lastname: Walse
authors.forename: Thomas
authors.initials: T
authors.lastname: Hünig
authors.forename: Poul
authors.initials: P
authors.lastname: Sørensen
authors.forename: David I
authors.initials: DI
authors.lastname: Stuart
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Davis
mesh_terms: D000069594:Abatacept; D000595:Amino Acid Sequence; D000818:Animals; D018106:CD28 Antigens / Q000737:chemistry* / Q000235:genetics / Q000276:immunology; D003461:Crystallography; D018796:Immunoconjugates / Q000378:metabolism; D007140:Immunoglobulin Fab Fragments / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016415:Sequence Alignment
chemical_list: D018106:CD28 Antigens; D018796:Immunoconjugates; D007140:Immunoglobulin Fab Fragments; D008024:Ligands; D000069594:Abatacept