γ-Protocadherin structural diversity and functional implications
- Columbia University, United States
Abstract
Stochastic cell-surface expression of α-, β-, and γ-clustered protocadherins (Pcdhs) provides vertebrate neurons with single-cell identities that underlie neuronal self-recognition. Here we report crystal structures of ectodomain fragments comprising cell-cell recognition regions of mouse γ-Pcdhs γA1, γA8, γB2, and γB7 revealing trans-homodimers, and of C-terminal ectodomain fragments from γ-Pcdhs γA4 and γB2, which depict cis-interacting regions in monomeric form. Together these structures span the entire Pcdhγ ectodomain. The trans-dimer structures reveal determinants of Pcdh-γ isoform-specific homophilic recognition. We identified and structurally mapped cis-dimerization mutations to the C-terminal ectodomain structures. Biophysical studies showed that Pcdh ectodomains from γB-subfamily isoforms formed cis dimers, whereas γA isoforms did not, but both γA and γB isoforms could interact in cis with α-Pcdhs. Together, these data show how interaction specificity is distributed over all domains of the γ-Pcdh trans interface, and suggest that subfamily- or isoform-specific cis-interactions may play a role in the Pcdh-mediated neuronal self-recognition code.
Data availability
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Protocadherin gamma A1 extracellular cadherin domains 1-4Publicly available at the RCSB Protein Data Bank (accession no. 5SZL).
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Protocadherin gamma A8 extracellular cadherin domains 1-4Publicly available at the RCSB Protein Data Bank (accession no. 5SZM).
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Protocadherin gamma A9 extracellular cadherin domains 1-5Publicly available at the RCSB Protein Data Bank (accession no. 5SZN).
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Protocadherin Gamma B7 extracellular cadherin domains 1-4 P41212 crystal formPublicly available at the RCSB Protein Data Bank (accession no. 5SZO).
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Protocadherin Gamma B7 extracellular cadherin domains 1-4 P21 crystal formPublicly available at the RCSB Protein Data Bank (accession no. 5SZP).
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Protocadherin gamma A4 extracellular cadherin domains 3-6Publicly available at the RCSB Protein Data Bank (accession no. 5SZQ).
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Protocadherin Gamma B2 extracellular cadherin domains 3-6Publicly available at the RCSB Protein Data Bank (accession no. 5SZR).
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Protocadherin Gamma B2 extracellular cadherin domains 1-5Publicly available at the RCSB Protein Data Bank (accession no. 5T9T).
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Structure of mouse clustered PcdhgA1 EC1-3Publicly available at the RCSB Protein Data Bank (accession no. 4ZI9).
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Crystal Structure of Protocadherin Gamma A8 EC1-3Publicly available at the RCSB Protein Data Bank (accession no. 4ZPS).
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Protocadherin alpha 7 extracellular cadherin domains 1-5Publicly available at the RCSB Protein Data Bank (accession no. 5DZV).
Article and author information
Author details
Funding
National Institutes of Health (R01GM107571)
- Tom Maniatis
- Lawrence Shapiro
Howard Hughes Medical Institute (R01GM062270)
- Fabiana Bahna
- Barry Honig
National Science Foundation (MCB-1412472)
- Barry Honig
Howard Hughes Medical Institute
- Fabiana Bahna
- Göran Ahlsén
- Barry Honig
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- William I Weis, Stanford University Medical Center, United States
Version history
- Received: August 23, 2016
- Accepted: October 6, 2016
- Accepted Manuscript published: October 26, 2016 (version 1)
- Version of Record published: November 11, 2016 (version 2)
Copyright
© 2016, Goodman et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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γ-Protocadherin structural diversity and functional implications
eLife 5:e20930.
https://doi.org/10.7554/eLife.20930
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