Clustered Protocadherin Molecular Assembly and Implications for Neuronal Self-Avoidance

Subsets of clustered protocadherin isoforms (α-, β-, and γ-Pcdhs) are stochastically expressed in individual vertebrate neurons.These cell-surface proteins provide a basis for neuronal self-recognition and non-self discrimination, which underpin neuronal selfavoidance.Using cell aggregation assays, X-ray crystallography, cryo-electron microscopy, biophysical measurements, and computational modeling, we have determined much of the molecular logic by which Pcdhs mediate neuronal self-vs-nonself-discrimination.Pcdh isoforms mediate cell-cell recognition through strictly homophilic trans-interactions involving extracellular cadherin domains 1-4 (EC1-4).Crystal structures of multiple α-, β-, and γ-isoforms revealed the molecular basis of their homophilic specificity.Pcdh isoforms also associate promiscuously in cis via their membrane-proximal EC5-6 domains, generating cis-dimeric recognition units.Coupling of Pcdh cis and trans interactions results in the formation of a zipper-like assembly between contacting cell surfaces.Computational experiments showed that the size of this assembly is very sensitive to the presence of mismatched isoforms between contacting cell surfaces, suggesting a mechanism for self-vs-non-self-discrimination among vertebrate neurons.