Nectin ectodomain structures reveal a canonical adhesive interface

Nectins are immunoglobulin superfamily glycoproteins that mediate intercellular adhesion in many vertebrate tissues. Homophilic and heterophilic interactions between nectin family members help to mediate tissue patterning. We determined homophilic binding affinities and heterophilic specificities of all four nectins and the related protein nectin-like 5 from human and mouse, revealing a range of homophilic strengths and a defined heterophilic specificity pattern. To understand the molecular basis of adhesion and specificity, we determined crystal structures of natively glycosylated full ectodomains or adhesive fragments of nectins 1–4 and nectin-like 5. All crystal structures reveal dimeric nectins bound through a stereotyped interface previously proposed to represent a cis dimer. However, conservation of this interface and results of targeted cross-linking experiments show that this dimer likely represents the adhesive trans interaction. Its structure provides a simple molecular explanation for the adhesive binding specificity of nectins.