Visualization of clustered protocadherin neuronal self-recognition complexes View Full Text


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Article Info

DATE

2019-04-10

AUTHORS

Julia Brasch, Kerry M. Goodman, Alex J. Noble, Micah Rapp, Seetha Mannepalli, Fabiana Bahna, Venkata P. Dandey, Tristan Bepler, Bonnie Berger, Tom Maniatis, Clinton S. Potter, Bridget Carragher, Barry Honig, Lawrence Shapiro

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. More... »

PAGES

280-283

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/s41586-019-1089-3

DOI

http://dx.doi.org/10.1038/s41586-019-1089-3

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1113356020

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/30971825


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20 schema:description 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.
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28 arrangement
29 array
30 assembly
31 autapses4
32 avoidance
33 cell surface expression
34 chain-termination model
35 chains11
36 cis
37 cis dimer
38 combination
39 complexes
40 configuration
41 contact sites
42 cryo-electron tomography
43 crystal structure
44 crystallography
45 dendritic
46 differences
47 dimer
48 ectodomain
49 expression
50 formation
51 formation of autapses4
52 free interaction
53 full-length protocadherin ectodomains
54 fundamental properties
55 homophilic trans
56 identical protocadherin
57 initial self-recognition step
58 interaction
59 interface
60 isoform-mismatch chain-termination model
61 isoform-promiscuous cis dimers
62 isoform-specific homophilic trans
63 isoforms
64 lattice
65 linear array
66 linear assemblies
67 linear chains11
68 liposomes
69 mammalian neurons
70 membrane
71 membrane contact sites
72 model
73 molecular arrangement
74 nervous systems1
75 neuronal avoidance
76 neuronal self-recognition complexes
77 neuronal surface
78 neurons
79 parallel arrays
80 process
81 properties
82 protocadherin ectodomains
83 protocadherin neuronal self-recognition complexes
84 protocadherin γB6 ectodomains
85 protocadherins
86 ray crystallography
87 results
88 self
89 self-recognition complexes
90 self-recognition step
91 single-isoform differences
92 single-isoform self-recognition complexes
93 sites
94 step
95 stochastic cell-surface expression
96 structure
97 support
98 surface
99 tomography
100 trans
101 trans interactions
102 two-dimensional structure
103 visualization
104 zipper-like lattice
105 γB6 ectodomains
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