Crystal structure of SLAM family members: implications for their costimulatory functions in T cell (88.9)

Abstract

Abstract Members of the signaling lymphocyte activation molecule (SLAM) family, including homophilic and heterophilic receptors, modulate a wide range of immune responses, including T cell activation and NK-cell activation. The SLAM family members share a similar ectodomain organization, with an N-terminal IgV domain and a C-terminal IgC2 domain. The sole exception is the Ly-9 ectodomain, which is composed of a tandem repeat of the IgV-IgC2 motif. The homophilic interaction is mediated by the first N-terminal IgV domain. The 2.0 Å crystal structures of the CD84 and Ly9 first N-terminal IgV domains reveal a similarly organized homophilic interaction with the recently reported NTB-A homophilic interaction, the differences in the homophilic interfaces is likely an important mechanistic feature that prevents the formation of undesired heterodimers among the SLAM family receptors. Notably our biochemical data also indicated the strong self association of CD84 and Ly9 with a Kd in the sub-micromolar range. The fact that the homophilic affinities span over three orders of magnitude among the SLAM family members suggests that the difference in the affinities might be a contributor to the different signaling behaviour exhibited by the individual family members.