Structural insights into the cis/trans dimerization of human DSCAM

Down Syndrome Cell Adhesion Molecule (DSCAM) belongs to the immunoglobulin (Ig) superfamily of cell-surface receptors and is implicated in cell adhesion and neuronal wiring. The Drosophila Dscam gene can give rise to more than 19,000 distinct ectodomain isoforms through differential splicing in three Ig domains, Ig2, Ig3, and Ig7. The diversity is used to generate a repertoire of homophilic interaction partners, exclusively amongst identical isoforms. This high degree of specificity in homophilic recognition is a key regulator of neurite self-avoidance in arthropods. The human genome contains two DSCAM genes (DSCAM and DSCAM-Like1), which do not undergo extensive alternative splicing. Nevertheless, Dscam and DSCAM share similar biological roles. Using X-ray crystallography, electron microscopy, and small-angle X-ray scattering, we have performed structural studies on human DSCAM to investigate whether homophilic dimerization is conserved between the species. Complementary binding and biophysical studies combined with site-directed mutagenesis suggest a possible mechanism for cis/trans dimerization, wherein the Ig7 domain plays a pivotal role.status: publishe