X-ray structure of junctional adhesion molecule: structural basis for homophilic adhesion via a novel dimerization motif

Junctional adhesion molecules (JAMs) are a family of immunoglobulin-like si ngle-span transmembrane molecules that are expressed in endothelial cells, epithelial cells, leukocytes and myocardia. JAM has been suggested to contr ibute to the adhesive function of tight junctions and to regulate leukocyte transmigration. We describe the crystal structure of the recombinant extra cellular part of mouse JAM (rsJAM) at 2.5 Angstrom resolution. rsJAM consis ts of two immunoglobulin-like domains that are connected by a conformationa lly restrained short linker. Two rsJAM molecules form a U-shaped dimer with highly complementary interactions between the N-terminal domains. Two salt bridges are formed in a complementary manner by a novel dimerization motif , R(V,I,L)E, which is essential for the formation of rsJAM dimers in soluti on and common to the known members of the JAM family. Based on the crystal packing and studies with mutant rsJAM, we propose a model for homophilic ad hesion of JAM. In this model, U-shaped JAM dimers are oriented in cis on th e cell surface and form a two-dimensional network by transinteractions of t heir N-terminal domains with JAM dimers from an opposite cell surface.