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Publication Abstract from PubMed

Neurite self-recognition and avoidance are fundamental properties of all nervous systems(1). These processes facilitate dendritic arborization(2,3), prevent formation of autapses(4) and allow free interaction among non-self neurons(1,2,4,5). Avoidance among self neurites is mediated by stochastic cell-surface expression of combinations of about 60 isoforms of alpha-, beta- and gamma-clustered protocadherin that provide mammalian neurons with single-cell identities(1,2,4-13). Avoidance is observed between neurons that express identical protocadherin repertoires(2,5), and single-isoform differences are sufficient to prevent self-recognition(10). Protocadherins form isoform-promiscuous cis dimers and isoform-specific homophilic trans dimers(10,14-20). Although these interactions have previously been characterized in isolation(15,17-20), structures of full-length protocadherin ectodomains have not been determined, and how these two interfaces engage in self-recognition between neuronal surfaces remains unknown. Here we determine the molecular arrangement of full-length clustered protocadherin ectodomains in single-isoform self-recognition complexes, using X-ray crystallography and cryo-electron tomography. We determine the crystal structure of the clustered protocadherin gammaB4 ectodomain, which reveals a zipper-like lattice that is formed by alternating cis and trans interactions. Using cryo-electron tomography, we show that clustered protocadherin gammaB6 ectodomains tethered to liposomes spontaneously assemble into linear arrays at membrane contact sites, in a configuration that is consistent with the assembly observed in the crystal structure. These linear assemblies pack against each other as parallel arrays to form larger two-dimensional structures between membranes. Our results suggest that the formation of ordered linear assemblies by clustered protocadherins represents the initial self-recognition step in neuronal avoidance, and thus provide support for the isoform-mismatch chain-termination model of protocadherin-mediated self-recognition, which depends on these linear chains(11).

Visualization of clustered protocadherin neuronal self-recognition complexes.,Brasch J, Goodman KM, Noble AJ, Rapp M, Mannepalli S, Bahna F, Dandey VP, Bepler T, Berger B, Maniatis T, Potter CS, Carragher B, Honig B, Shapiro L Nature. 2019 Apr 10. pii: 10.1038/s41586-019-1089-3. doi:, 10.1038/s41586-019-1089-3. PMID:30971825^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.