title: Identification of protein-protein interfaces implicated in CD80-CD28 costimulatory signaling.
abstract: 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.
authors.affiliation: Active Biotech Research, Lund, Sweden.
authors.forename: Poul
authors.initials: P
authors.lastname: Sørensen
authors.forename: Martin
authors.initials: M
authors.lastname: Kussmann
authors.forename: Anna
authors.initials: A
authors.lastname: Rosén
authors.forename: Keiryn L
authors.initials: KL
authors.lastname: Bennett
authors.forename: Dorthe da Graça
authors.initials: Dda G
authors.lastname: Thrige
authors.forename: Kristina
authors.initials: K
authors.lastname: Uvebrant
authors.forename: Björn
authors.initials: B
authors.lastname: Walse
authors.forename: Peter
authors.initials: P
authors.lastname: Roepstorff
authors.forename: Per
authors.initials: P
authors.lastname: Björk
mesh_terms: 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
chemical_list: D015703:Antigens, CD; D000943:Antigens, Differentiation; D018122:B7-1 Antigen; D018106:CD28 Antigens; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human