Crystal structure of the receptor-binding domain of human B7-2: insights into organization and signaling.
B7-1 and B7-2 are homologous costimulatory ligands expressed on the surfaces of antigen-presenting cells. Their interactions with CD28/CTLA-4 receptors expressed on T cell surfaces are crucial for the proper regulation of T cell activity. B7-1 and B7-2 display distinct roles in immune regulation, although they are usually considered to have redundant functions. Here, we report the crystal structure of the receptor-binding (Ig V-type) domain of human B7-2 at 2.7-A resolution. Structures of unliganded and liganded B7-1 and B7-2 suggest a physical-chemical basis for the observed functional similarities and differences between these two costimulatory ligands. Of particular note, whereas the majority of the residues mediating B7-1 dimerization are hydrophobic, the B7-2 dimer observed in the B7-2/CTLA-4 complex displays a very hydrophilic dimer interface. These differences provide a mechanism for preventing the formation of B7-1/B7-2 heterodimers. The divergence at the putative dimer interface is also consistent with the lower tendency of B7-2 to dimerize, as shown by the monomeric state of unliganded B7-2 both in solution and crystalline form, and may result in detailed differences in signaling mechanisms associated with B7-1 and B7-2.
Zhang
Xuewu
X
Department of Cell Biology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA.
Schwartz
Jean-Claude D
JC
Almo
Steven C
SC
Nathenson
Stanley G
SG
D000069594:Abatacept; D000595:Amino Acid Sequence; D015703:Antigens, CD / Q000737:chemistry* / Q000378:metabolism*; D000943:Antigens, Differentiation / Q000096:biosynthesis; D018122:B7-1 Antigen / Q000737:chemistry; D051940:B7-2 Antigen; D018106:CD28 Antigens / Q000096:biosynthesis; D060908:CTLA-4 Antigen; D018360:Crystallography, X-Ray; D019281:Dimerization; D006801:Humans; D018796:Immunoconjugates; D008024:Ligands; D008562:Membrane Glycoproteins / Q000737:chemistry* / Q000378:metabolism*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011485:Protein Binding; D017510:Protein Folding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D014461:Ultracentrifugation
D015703:Antigens, CD; D000943:Antigens, Differentiation; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D018106:CD28 Antigens; C497964:CD86 protein, human; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D018796:Immunoconjugates; D008024:Ligands; D008562:Membrane Glycoproteins; D000069594:Abatacept