Structure and Interactions of NCAM Ig1-2-3 Suggest a Novel Zipper Mechanism for Homophilic Adhesion

The neural cell adhesion molecule, NCAM, mediates Ca 2+-independent cell-cell and cell-substratum adhesion via homophilic (NCAM-NCAM) and heterophilic (NCAM-non-NCAM molecules) binding. NCAM plays a key role in neural development, regeneration, and synaptic plasticity, including learning and memory consolidation. The crystal structure of a fragment comprising the three N-terminal Ig modules of rat NCAM has been determined to 2.0 Å resolution. Based on crystallographic data and biological experiments we present a novel model for NCAM homophilic binding. The Ig1 and Ig2 modules mediate dimerization of NCAM molecules situated on the same cell surface ( cis interactions), whereas the Ig3 module mediates interactions between NCAM molecules expressed on the surface of opposing cells ( trans interactions) through simultaneous binding to the Ig1 and Ig2 modules. This arrangement results in two perpendicular zippers forming a double zipper-like NCAM adhesion complex.