title: Rigid-body ligand recognition drives cytotoxic T-lymphocyte antigen 4 (CTLA-4) receptor triggering.
abstract: The inhibitory T-cell surface-expressed receptor, cytotoxic T lymphocyte-associated antigen-4 (CTLA-4), which belongs to the class of cell surface proteins phosphorylated by extrinsic tyrosine kinases that also includes antigen receptors, binds the related ligands, B7-1 and B7-2, expressed on antigen-presenting cells. Conformational changes are commonly invoked to explain ligand-induced "triggering" of this class of receptors. Crystal structures of ligand-bound CTLA-4 have been reported, but not the apo form, precluding analysis of the structural changes accompanying ligand binding. The 1.8-Å resolution structure of an apo human CTLA-4 homodimer emphasizes the shared evolutionary history of the CTLA-4/CD28 subgroup of the immunoglobulin superfamily and the antigen receptors. The ligand-bound and unbound forms of both CTLA-4 and B7-1 are remarkably similar, in marked contrast to B7-2, whose binding to CTLA-4 has elements of induced fit. Isothermal titration calorimetry reveals that ligand binding by CTLA-4 is enthalpically driven and accompanied by unfavorable entropic changes. The similarity of the thermodynamic parameters determined for the interactions of CTLA-4 with B7-1 and B7-2 suggests that the binding is not highly specific, but the conformational changes observed for B7-2 binding suggest some level of selectivity. The new structure establishes that rigid-body ligand interactions are capable of triggering CTLA-4 phosphorylation by extrinsic kinase(s).
authors.affiliation: Nuffield Department of Clinical Medicine and MRC Human Immunology Unit, The University of Oxford, John Radcliffe Hospital, Headington, Oxford OX3 9DU, United Kingdom.
authors.forename: Chao
authors.initials: C
authors.lastname: Yu
authors.forename: Andreas F-P
authors.initials: AF
authors.lastname: Sonnen
authors.forename: Roger
authors.initials: R
authors.lastname: George
authors.forename: Benoit H
authors.initials: BH
authors.lastname: Dessailly
authors.forename: Loren J
authors.initials: LJ
authors.lastname: Stagg
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Evans
authors.forename: Christine A
authors.initials: CA
authors.lastname: Orengo
authors.forename: David I
authors.initials: DI
authors.lastname: Stuart
authors.forename: John E
authors.initials: JE
authors.lastname: Ladbury
authors.forename: Shinji
authors.initials: S
authors.lastname: Ikemizu
authors.forename: Robert J C
authors.initials: RJ
authors.lastname: Gilbert
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Davis
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000737:chemistry* / Q000235:genetics / Q000276:immunology; D018122:B7-1 Antigen / Q000737:chemistry* / Q000235:genetics / Q000276:immunology; D051940:B7-2 Antigen / Q000737:chemistry* / Q000235:genetics / Q000276:immunology; D001665:Binding Sites; D016466:CHO Cells; D060908:CTLA-4 Antigen; D006224:Cricetinae; D003412:Cricetulus; D018360:Crystallography, X-Ray; D006801:Humans; D017434:Protein Structure, Tertiary; D011948:Receptors, Antigen, T-Cell / Q000737:chemistry* / Q000235:genetics / Q000276:immunology; D013816:Thermodynamics
chemical_list: D015703:Antigens, CD; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D011948:Receptors, Antigen, T-Cell