How clustered protocadherin binding specificity is tuned for neuronal self/non-self-recognition

Abstract

The stochastic expression of fewer than 60 clustered protocadherin (cPcdh) isoforms provides diverse identities to individual vertebrate neurons and a molecular basis for self/non-self-discrimination. cPcdhs form chains mediated by alternating cis and trans interactions between apposed membranes, which has been suggested to signal self-recognition. Such a mechanism requires that cPcdh cis dimers form promiscuously to generate diverse recognition units, and that trans interactions have precise specificity so that isoform mismatches terminate chain growth. However, the extent to which cPcdh interactions fulfill these requirements has not been definitively demonstrated. Here we report biophysical experiments showing that cPcdh cis interactions are promiscuous, but with preferences favoring formation of heterologous cis dimers. Trans-homophilic interactions are remarkably precise, with no evidence for heterophilic interactions between different isoforms. A new C-type cPcdh crystal structure and mutagenesis data help to explain these observations. Overall, the interaction characteristics we report for cPcdhs help explain their function in neuronal self/non-self-discrimination

Trans-splicing facilitated by RNA pairing greatly expands sDscam isoform diversity but not homophilic binding specificity

“…martensii ( 34 ), in which the constant region affects the formation and size of cell aggregates. Biophysical experiments showed that cis interactions of cPcdh are generally promiscuous but with a preference for the formation of heterologous cis dimers ( 59 ). If this finding holds true in the sDscam family, we would expect that differences in the constant region would affect cis interactions.…”