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Visualization of clustered protocadherin neuronal self-recognition complexes

Author(s)
Brasch, Julia; Goodman, Kerry M.; Noble, Alex J.; Rapp, Micah; Mannepalli, Seetha; Bahna, Fabiana; Dandey, Venkata P.; Bepler, Tristan; Berger Leighton, Bonnie; Maniatis, Tom; Potter, Clinton S.; Carragher, Bridget; Honig, Barry; Shapiro, Lawrence; ... Show more Show less
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Abstract
Neurite self-recognition and avoidance are fundamental properties of all nervous systems. These processes facilitate dendritic arborization, prevent formation of autapses and allow free interaction among non-self neurons. Avoidance among self neurites is mediated by stochastic cell-surface expression of combinations of about 60 isoforms of α-, β- and γ-clustered protocadherin that provide mammalian neurons with single-cell identities. Avoidance is observed between neurons that express identical protocadherin repertoires2,5, and single-isoform differences are sufficient to prevent self-recognition10. Protocadherins form isoform-promiscuous cis dimers and isoform-specific homophilic trans dimers. Although these interactions have previously been characterized in isolation, 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 γB4 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 γB6 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. Keywords: cryoelectron tomography; molecular neuroscience; x-ray crystallography
Date issued
2019-04-10
URI
https://hdl.handle.net/1721.1/122924
Department
Massachusetts Institute of Technology. Department of Mathematics; Massachusetts Institute of Technology. Computational and Systems Biology Program; Massachusetts Institute of Technology. Computer Science and Artificial Intelligence Laboratory
Journal
Nature
Publisher
Springer Science and Business Media LLC
Citation
Brasch, J., et al. "Visualization of clustered protocadherin neuronal self-recognition complexes." Nature 569, 7755 (May 2019): 280–283 © 2019 Springer Nature Limited
Version: Author's final manuscript
ISSN
0028-0836
1476-4687

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