Author
Listed:
- Julia Brasch
(Columbia University
The National Resource for Automated Molecular Microscopy
Columbia University)
- Kerry M. Goodman
(Columbia University
Columbia University)
- Alex J. Noble
(The National Resource for Automated Molecular Microscopy)
- Micah Rapp
(Columbia University
The National Resource for Automated Molecular Microscopy
Columbia University)
- Seetha Mannepalli
(Columbia University
Columbia University)
- Fabiana Bahna
(Columbia University
Columbia University
Columbia University)
- Venkata P. Dandey
(The National Resource for Automated Molecular Microscopy)
- Tristan Bepler
(MIT
MIT)
- Bonnie Berger
(MIT
MIT)
- Tom Maniatis
(Columbia University
Columbia University)
- Clinton S. Potter
(The National Resource for Automated Molecular Microscopy
Columbia University)
- Bridget Carragher
(The National Resource for Automated Molecular Microscopy
Columbia University)
- Barry Honig
(Columbia University
Columbia University
Columbia University
Columbia University)
- Lawrence Shapiro
(Columbia University
Columbia University
Columbia University)
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.
Suggested Citation
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 Carra, 2019.
"Visualization of clustered protocadherin neuronal self-recognition complexes,"
Nature, Nature, vol. 569(7755), pages 280-283, May.
Handle:
RePEc:nat:nature:v:569:y:2019:i:7755:d:10.1038_s41586-019-1089-3
DOI: 10.1038/s41586-019-1089-3
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Cited by:
- Elliot Medina & Yathreb Easa & Daniel K. Lester & Eric K. Lau & David Sprinzak & Vincent C. Luca, 2023.
"Structure of the planar cell polarity cadherins Fat4 and Dachsous1,"
Nature Communications, Nature, vol. 14(1), pages 1-11, December.
- D. Halperin & A. Stavsky & R. Kadir & M. Drabkin & O. Wormser & Y. Yogev & V. Dolgin & R. Proskorovski-Ohayon & Y. Perez & H. Nudelman & O. Stoler & B. Rotblat & T. Lifschytz & A. Lotan & G. Meiri & D, 2021.
"CDH2 mutation affecting N-cadherin function causes attention-deficit hyperactivity disorder in humans and mice,"
Nature Communications, Nature, vol. 12(1), pages 1-19, December.
- Jie Cheng & Yamei Yu & Xingyu Wang & Xi Zheng & Ting Liu & Daojun Hu & Yongfeng Jin & Ying Lai & Tian-Min Fu & Qiang Chen, 2023.
"Structural basis for the self-recognition of sDSCAM in Chelicerata,"
Nature Communications, Nature, vol. 14(1), pages 1-12, December.
- Xiao Ge & Haiyan Huang & Keqi Han & Wangjie Xu & Zhaoxia Wang & Qiang Wu, 2023.
"Outward-oriented sites within clustered CTCF boundaries are key for intra-TAD chromatin interactions and gene regulation,"
Nature Communications, Nature, vol. 14(1), pages 1-13, December.
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