부산대학교 도서관

Neurite self-recognition and avoidance are fundamental properties of all nervous systems.sup.1. These processes facilitate dendritic arborization.sup.2,3, prevent formation of autapses.sup.4 and allow free interaction among non-self neurons.sup.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.sup.1,2,4-13. Avoidance is observed between neurons that express identical protocadherin repertoires.sup.2,5, and single-isoform differences are sufficient to prevent self-recognition.sup.10. Protocadherins form isoform-promiscuous cis dimers and isoform-specific homophilic trans dimers.sup.10,14-20. Although these interactions have previously been characterized in isolation.sup.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 [gamma]B4 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 [gamma]B6 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.sup.11. Clustered protocadherin ectodomains spontaneously assemble to form a zipper-like lattice of alternating cis and trans interactions at membrane contact sites, which probably represents their mode of function in neuronal self-recognition.
Author(s): Julia Brasch [sup.1] [sup.2] [sup.3] , Kerry M. Goodman [sup.1] [sup.3] , Alex J. Noble [sup.2] , Micah Rapp [sup.1] [sup.2] [sup.3] , Seetha Mannepalli [sup.1] [sup.3] , Fabiana [...]