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Nature. 2019 May;569(7755):280-283. doi: 10.1038/s41586-019-1089-3. Epub 2019 Apr 10.

Visualization of clustered protocadherin neuronal self-recognition complexes.

Brasch J1,2,3, Goodman KM1,3, Noble AJ2, Rapp M1,2,3, Mannepalli S1,3, Bahna F1,4,5, Dandey VP2, Bepler T6,7, Berger B7,8, Maniatis T1,3, Potter CS2,3, Carragher B2,3, Honig B9,10,11,12,13, Shapiro L14,15,16.

Author information

1
Zuckerman Mind, Brain and Behavior Institute, Columbia University, New York, NY, USA.
2
Simons Electron Microscopy Center, New York Structural Biology Center, The National Resource for Automated Molecular Microscopy, New York, NY, USA.
3
Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY, USA.
4
Howard Hughes Medical Institute, Columbia University, New York, NY, USA.
5
Department of Systems Biology, Columbia University, New York, NY, USA.
6
Computational and Systems Biology, MIT, Cambridge, MA, USA.
7
Computer Science and Artificial Intelligence Laboratory, MIT, Cambridge, MA, USA.
8
Department of Mathematics, MIT, Cambridge, MA, USA.
9
Zuckerman Mind, Brain and Behavior Institute, Columbia University, New York, NY, USA. bh6@cumc.columbia.edu.
10
Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY, USA. bh6@cumc.columbia.edu.
11
Howard Hughes Medical Institute, Columbia University, New York, NY, USA. bh6@cumc.columbia.edu.
12
Department of Systems Biology, Columbia University, New York, NY, USA. bh6@cumc.columbia.edu.
13
Department of Medicine, Columbia University, New York, NY, USA. bh6@cumc.columbia.edu.
14
Zuckerman Mind, Brain and Behavior Institute, Columbia University, New York, NY, USA. lss8@columbia.edu.
15
Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY, USA. lss8@columbia.edu.
16
Department of Systems Biology, Columbia University, New York, NY, USA. lss8@columbia.edu.

Abstract

Neurite self-recognition and avoidance are fundamental properties of all nervous systems1. These processes facilitate dendritic arborization2,3, prevent formation of autapses4 and allow free interaction among non-self neurons1,2,4,5. 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 identities1,2,4-13. 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 dimers10,14-20. Although these interactions have previously been characterized in isolation15,17-20, 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 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 chains11.

PMID:
30971825
DOI:
10.1038/s41586-019-1089-3

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