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Identification of Protein-Protein Interfaces Implicated in CD80-CD28 Costimulatory Signaling

Poul Sørensen^1,*, Martin Kussmann^2,, Anna Rosén^*, Keiryn L. Bennett^3,, Dorthe da Graça Thrige^*, Kristina Uvebrant^*, Björn Walse^*, Peter Roepstorff and Per Björk^4,*

^* Active Biotech Research, Lund, Sweden; and Institute for Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark

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.

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				K. Uvebrant, D. Da Graca Thrige, A. Rosen, M. Akesson, H. Berg, B. Walse, and P. Bjork Discovery of Selective Small-Molecule CD80 Inhibitors J Biomol Screen, June 1, 2007; 12(4): 464 - 472. [Abstract] [PDF]