A double S shape provides the structural basis for the extraordinary binding specificity of Dscam isoforms

Drosophila Dscam encodes a vast family of immunoglobulin (Ig)-containing proteins that exhibit isoform-specific homophilic binding. This diversity is essential for cell recognition events required for wiring the brain. Each isoform binds to itself but rarely to other isoforms. Specificity is determined by matching'' of three variable Ig domains within an similar to 220 kD ectodomain. Here, we present the structure of the homophilic binding region of Dscam, comprising the eight N-terminal Ig domains (Dscam(1-8)). Dscam(1-8) forms a symmetric homodimer of S-shaped molecules. This conformation, comprising two reverse turns, allows each pair of the three variable domains to match'' in an antiparallel fashion. Structural, genetic, and biochemical studies demonstrate that, in addition to variable domain matching,'' intramolecular interactions between constant domains promote homophilic binding. These studies provide insight into how matching'' at all three pairs of variable domains in Dscam mediates isoform-specific recognition.