Structure of Nectin-2 reveals determinants of homophilic and heterophilic interactions that control cell-cell adhesion and immune regulation (176.10)

Abstract

Abstract Nectin comprises a family of four immunoglobulin-like molecules. Homophilic and heterophilic interactions among nectins are implicated in cell-cell adhesion, while their interactions with members of other protein families have diverse biological functions like host-pathogen interaction and immune modulation. In particular, nectin-2, found to be up-regulated on cancer cells is capable of interacting with two receptors, CD226 and TIGIT, expressed on T and NK cells. These interactions lead to the delivery of two opposing signals to both T and NK cells. This situation is reminiscent of the well-studied pathways in T cells, in which the coinhibitory receptor CTLA-4 binds the same ligand (B7) as the coactivating receptor CD28. In order to define the molecular and structural determinants underlying the homophilic and heterophilic recognitions of nectin-2, we examined the biochemical, biophysical and structural properties of human nectin-2. The structure of nectin-2 at 1.3 Å resolution reveals that the architecture of the nectin-2 homophilic dimer resembles other members of the immunoglobulin superfamily and defines the details responsible for recognition and selectivity. Of particular note, the close proximity of charged residues at the interface is a major determinant of binding affinity. Using these biochemical and structural data, we also characterized the heterophilic binding of nectin-2 with TIGIT, which is implicated in T cell and NK cell-mediated immune modulation.