Rigid-body ligand recognition drives cytotoxic T-lymphocyte antigen 4 (CTLA-4) receptor triggering.

Journal article

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: Yu, C; Sonnen, A; George, R; Dessailly, B; Stagg, L

• Publication status: Published
• Journal: Journal of biological chemistry
• Volume: 286
• Issue: 8
• Pages: 6685-6696
• Publication date: 2011-02-01
• DOI: 10.1074/jbc.m110.182394
• EISSN: 1083-351X
• ISSN: 0021-9258
• Language: English
• Keywords: Humans; Crystallography, X-Ray; CHO Cells; Thermodynamics; Protein Structure, Tertiary; Antigens, CD86; Receptors, Antigen, T-Cell; Cricetinae; Antigens, CD; CTLA-4 Antigen; Animals; Binding Sites; Cricetulus; Antigens, CD80