Structure and Dimerization of a Soluble Form of B7-1

Abstract

B7-1 (CD80) and B7-2 (CD86) are glycoproteins expressed on antigen-presenting cells. The binding of these molecules to the T cell homodimers CD28 and CTLA-4 (CD152) generates costimulatory and inhibitory signals in T cells, respectively. The crystal structure of the extracellular region of B7-1 (sB7-1), solved to 3 A resolution, consists of a novel combination of two Ig-like domains, one characteristic of adhesion molecules and the other previously seen only in antigen receptors. In the crystal lattice, sB7-1 unexpectedly forms parallel, 2-fold rotationally symmetric homodimers. Analytical ultracentrifugation reveals that sB7-1 also dimerizes in solution. The structural data suggest a mechanism whereby the avidity-enhanced binding of B7-1 and CTLA-4 homodimers, along with the relatively high affinity of these interactions, favors the formation of very stable inhibitory signaling complexes.

Inhibition of RON kinase potentiates anti-CTLA-4 immunotherapy to shrink breast tumors and prevent metastatic outgrowth

“…71 CD80 was shown to have a higher affinity to CTLA-4, when compared to CD86. 70,72 Using in vivo models, others have shown that the molecular signals delivered by CD80 and CD86 are not necessarily redundant. For instance, CD80 expressed in leukemic cells was found to suppress T cell immunity while CD86 was unable to do so.…”

The impact of protein characterization in structural proteomics

“…In the case of B7-1, the crystallographic dimer was shown to form in solution (Ikemizu et al, 2000). This permitted the development of models of interaction between B7-1 and CTLA-4 involving avidity enhancement of cell-cell interaction through the formation of extended zipperlike regions of attachment (Ikemizu et al, 2000;Stamper et al, 2001).…”

“…In the case of B7-1, the crystallographic dimer was shown to form in solution (Ikemizu et al, 2000). This permitted the development of models of interaction between B7-1 and CTLA-4 involving avidity enhancement of cell-cell interaction through the formation of extended zipperlike regions of attachment (Ikemizu et al, 2000;Stamper et al, 2001). AUC was used to show in addition that the homologous B7-2 is instead monomeric, thus being weakly stimulatory of a T-cell response whereas B7-1 is strongly inhibitory (Collins et al, 2002).…”

Structures of PD-1 with its ligands: Sideways and dancing cheek to cheek

“…The structures show a 1:1 receptor/ligand stoichiometry, with interaction primarily between the faces of the IgV domains. PD-1, PD-L1, and PD-L2 are monomers in the crystal and on the cell surface unlike B7-1, CD28, and CTLA4, which are noncovalent and covalent dimers, respectively (11,12). An IgV domain is composed of Ϸ120 aa organized into nine parallel ␤-strands (ABCCЈCЉDEFG) with loops connecting the strands.…”

“…Although the complete structure of PD-L2 with ligand was determined, the structure of free PD-L2 is only of the IgV domain. B7-1 is a rigid rod with a very similar structure alone or bound to CTLA4 (11,12). In contrast, the IgV and IgC domains of PD-L1 are in a straight line when complexed with PD-1 but diverge 38°from straight without PD-1 (5).…”