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Title: Structural Basis of Diverse Homophilic Recognition by Clustered α- and β-Protocadherins

Abstract

Clustered protocadherin proteins (α-, β-, and γ-Pcdhs) provide a high level of cell-surface diversity to individual vertebrate neurons, engaging in highly specific homophilic interactions to mediate important roles in mammalian neural circuit development. How Pcdhs bind homophilically through their extracellular cadherin (EC) domains among dozens of highly similar isoforms has not been determined. Here, we report crystal structures for extracellular regions from four mouse Pcdh isoforms (α4, α7, β6, and β8), revealing a canonical head-to-tail interaction mode for homophilic trans dimers comprising primary intermolecular EC1:EC4 and EC2:EC3 interactions. A subset of trans interface residues exhibit isoform-specific conservation, suggesting roles in recognition specificity. Mutation of these residues, along with trans-interacting partner residues, altered the specificities of Pcdh interactions. Altogether, these data show how sequence variation among Pcdh isoforms encodes their diverse strict homophilic recognition specificities, which are required for their key roles in neural circuit assembly.

Authors:
 [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1]
  1. Columbia Univ., New York, NY (United States)
Publication Date:
Research Org.:
Argonne National Laboratory (ANL), Argonne, IL (United States)
Sponsoring Org.:
National Institutes of Health (NIH); National Science Foundation (NSF)
OSTI Identifier:
1255307
Grant/Contract Number:  
P41 GM103403; MCB-1412472; R01GM062270; R01GM107571
Resource Type:
Accepted Manuscript
Journal Name:
Neuron
Additional Journal Information:
Journal Volume: 90; Journal Issue: 4; Journal ID: ISSN 0896-6273
Publisher:
Cell Press - Elsevier
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES

Citation Formats

Goodman, Kerry  Marie, Rubinstein, Rotem, Thu, Chan  Aye, Bahna, Fabiana, Mannepalli, Seetha, Ahlsén, Göran, Rittenhouse, Chelsea, Maniatis, Tom, Honig, Barry, and Shapiro, Lawrence. Structural Basis of Diverse Homophilic Recognition by Clustered α- and β-Protocadherins. United States: N. p., 2016. Web. doi:10.1016/j.neuron.2016.04.004.
Goodman, Kerry  Marie, Rubinstein, Rotem, Thu, Chan  Aye, Bahna, Fabiana, Mannepalli, Seetha, Ahlsén, Göran, Rittenhouse, Chelsea, Maniatis, Tom, Honig, Barry, & Shapiro, Lawrence. Structural Basis of Diverse Homophilic Recognition by Clustered α- and β-Protocadherins. United States. https://doi.org/10.1016/j.neuron.2016.04.004
Goodman, Kerry  Marie, Rubinstein, Rotem, Thu, Chan  Aye, Bahna, Fabiana, Mannepalli, Seetha, Ahlsén, Göran, Rittenhouse, Chelsea, Maniatis, Tom, Honig, Barry, and Shapiro, Lawrence. Thu . "Structural Basis of Diverse Homophilic Recognition by Clustered α- and β-Protocadherins". United States. https://doi.org/10.1016/j.neuron.2016.04.004. https://www.osti.gov/servlets/purl/1255307.
@article{osti_1255307,
title = {Structural Basis of Diverse Homophilic Recognition by Clustered α- and β-Protocadherins},
author = {Goodman, Kerry  Marie and Rubinstein, Rotem and Thu, Chan  Aye and Bahna, Fabiana and Mannepalli, Seetha and Ahlsén, Göran and Rittenhouse, Chelsea and Maniatis, Tom and Honig, Barry and Shapiro, Lawrence},
abstractNote = {Clustered protocadherin proteins (α-, β-, and γ-Pcdhs) provide a high level of cell-surface diversity to individual vertebrate neurons, engaging in highly specific homophilic interactions to mediate important roles in mammalian neural circuit development. How Pcdhs bind homophilically through their extracellular cadherin (EC) domains among dozens of highly similar isoforms has not been determined. Here, we report crystal structures for extracellular regions from four mouse Pcdh isoforms (α4, α7, β6, and β8), revealing a canonical head-to-tail interaction mode for homophilic trans dimers comprising primary intermolecular EC1:EC4 and EC2:EC3 interactions. A subset of trans interface residues exhibit isoform-specific conservation, suggesting roles in recognition specificity. Mutation of these residues, along with trans-interacting partner residues, altered the specificities of Pcdh interactions. Altogether, these data show how sequence variation among Pcdh isoforms encodes their diverse strict homophilic recognition specificities, which are required for their key roles in neural circuit assembly.},
doi = {10.1016/j.neuron.2016.04.004},
journal = {Neuron},
number = 4,
volume = 90,
place = {United States},
year = {Thu May 05 00:00:00 EDT 2016},
month = {Thu May 05 00:00:00 EDT 2016}
}

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