Neuronal `barcodes` - Protocadherins Cis and Trans interactions generate oligomeric complexes that are neuron-specific

In the developing brain, the process of assembling a healthy and functional neural circuitry requires billions of neurons to find their appropriate targets, while avoiding improper connections. Self-avoidance occurs when neurites, originating from the same cell, selectively avoid each other while overlapping with other neurons. This process is critical in segregating axon branches and in dendritic field development for both vertebrates and invertebrates. Self-avoidance relies on a mechanism, whereby numerous neurons distinguish self from non-self, and therefore represents a complex problem in cell-cell recognition, as it depends on a limited repertoire of cell surface receptors. In vertebrates, clustered protocadherins, a family of approximately ~60 proteins mediates neuronal self-recognition and non-self discrimination, which underlies neuronal self-avoidance. High-resolution structures, along with biophysical and theoretical analyses, have shown that protocadherins interact with remarkable homophilic specificity and have suggested the formation of a linear zipper-like assembly at the cell-cell interface. Here we present a Monte-Carlo simulation of protocadherin interactions on the cell-membranes, which reveals unexpected architectural features that may govern recognition and signaling mechanisms. Our results recapitulate and are consistent with all available experimental data and suggest a new molecular basis for cell-cell recognition.