Rigid-body ligand recognition drives cytotoxic T-lymphocyte antigen 4 (CTLA-4) receptor triggering
Yu C, Sonnen AF, George R, Dessailly BH, Stagg LJ, Evans EJ, Orengo CA, Stuart DI, Ladbury JE, Ikemizu S, Gilbert RJ, Davis SJ. (2011), J Biol Chem. 286, 6685-96
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).
Key figure: Structural similarity dendrogram and heatmap for a selection of V-set IgSF domains, based on SSAP scores
Domains are identified by the common short names of the proteins in which they occur, with the identifier and chain letter for the PDB structure used for comparison in brackets. Domains were ordered according to a dendrogram constructed using complete hierarchical clustering based on scores obtained from pairwise structural comparisons using SSAP (43). Colors in the heatmap range from red to dark green for high and low structural similarity, respectively (see color key). A histogram in the color key panel shows the frequency distribution of SSAP scores in the set. Color bars on the left and upper sides of the heatmap indicate known functional or family groupings: green, CTLA-4; yellow, other members of the costimulatory/inhibitory family; red, antigen receptors;pink, coreceptors; dark blue, CD2 family; light blue, B7 family; black, outgroup (C1 and C2 set IgSF domains); gray, other V-set proteins.