CRYSTAL STRUCTURE OF THE NATURAL KILLER CELL RECEPTOR 2B4 IN COMPLEX WITH CD48

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. As part of innate immunity, natural killer (NK) cells are capable of killing certain tumor and virally infected cells. A fine balance between the activating and inhibitory receptors on the cells surface controls the cytolytic activity of NK cells. The inhibitory receptors provide the protection from lysis by recognizing class I MHC molecules on healthy host cells. Activating NK receptors mediate the killing of tumor or virally infected cells through specific ligand recognition. In contrast to the inhibitory receptors, much less is known about the structures of activating NK receptors. 2B4, a transmembrane receptor expressed primarily on NK cells and on a subset of CD8+ T cells, plays an important role in activating NK-mediated cytotoxicity through its interaction with CD48 on target cells. 2B4 comprises two Ig-like extracellular domains (D1 and D2) and a cytoplasmic portion containing a CxC/+ motif that may bind a complementary CxxC/¿¿¿ motif in the linker for activation of T cells (LAT). In addition to LAT, the cytoplasmic tail of 2B4 binds the SH2 domain-containing protein SAP. This association is crucial for 2B4 to deliver activating signals to NK cells. Indeed, in the absence of SAP, 2B4 tranduces inhibitory signals that result in NK cell inactivation. The finding that 2B4 can both activate and inhibit NK cytolysis, combined with the identification of CD48 as its biological ligand, make 2B4 a compelling target for structural analysis.