Identification of protein-protein interfaces implicated in CD80-CD28 costimulatory signaling.
The B7 ligands CD80 and CD86 on APCs deliver either costimulatory or inhibitory signals to the T cell when interacting with their counter-receptors CD28 and CD152 (CTLA-4) on the T cell surface. Although crucial for lymphocyte regulation, the structural basis of these interactions is still not completely understood. Using multivalent presentation and conditions mimicking clustering, believed to be essential for signaling through these receptors, and by applying a combined differential mass spectrometry and structural mapping approach to these conditions, we were able to identify a putative contact area involving hydrophilic regions on both CD28 and CD80 as well as a putative CD28 oligomerization interface induced by B7 ligation. Analysis of the CD80-CD28 interaction site reveals a well-defined interface structurally distinct from that of CD80 and CD152 and thus provides valuable information for therapeutic intervention targeted at this pathway, suggesting a general approach for other receptors.
Sørensen
Poul
P
Active Biotech Research, Lund, Sweden.
Kussmann
Martin
M
Rosén
Anna
A
Bennett
Keiryn L
KL
Thrige
Dorthe da Graça
Dda G
Uvebrant
Kristina
K
Walse
Björn
B
Roepstorff
Peter
P
Björk
Per
P
D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000737:chemistry; D018122:B7-1 Antigen / Q000737:chemistry* / Q000502:physiology; D018106:CD28 Antigens / Q000737:chemistry* / Q000502:physiology; D016466:CHO Cells; D060908:CTLA-4 Antigen; D006224:Cricetinae; D019281:Dimerization; D006801:Humans; D015398:Signal Transduction
D015703:Antigens, CD; D000943:Antigens, Differentiation; D018122:B7-1 Antigen; D018106:CD28 Antigens; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human