Molecular basis of sidekick-mediated cell-cell adhesion and specificity
- Columbia University, United States
- Harvard University, United States
- Michigan State University, United States
Abstract
Sidekick (Sdk) 1 and 2 are related immunoglobulin superfamily cell adhesion proteins required for appropriate synaptic connections between specific subtypes of retinal neurons. Sdks mediate cell-cell adhesion with homophilic specificity that underlies their neuronal targeting function. Here we report crystal structures of Sdk1 and Sdk2 ectodomain regions, revealing similar homodimers mediated by the four N-terminal immunoglobulin domains (Ig1-4), arranged in a horseshoe conformation. These Ig1-4 horseshoes interact in a novel back-to-back orientation in both homodimers through Ig1:Ig2, Ig1:Ig1 and Ig3:Ig4 interactions. Structure-guided mutagenesis results show that this canonical dimer is required for both Sdk-mediated cell aggregation (via trans interactions) and Sdk clustering in isolated cells (via cis interactions). Sdk1/Sdk2 recognition specificity is encoded across Ig1-4, with Ig1-2 conferring the majority of binding affinity and differential specificity. We suggest that competition between cis and trans interactions provides a novel mechanism to sharpen the specificity of cell-cell interactions.
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Author details
Funding
National Institutes of Health
- Lawrence Shapiro
Howard Hughes Medical Institute
- Xiangshu Jin
- Phinikoula S Katsamba
- Alina P Sergeeva
- Barry Honig
National Institutes of Health
- Joshua R Sanes
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
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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Molecular basis of sidekick-mediated cell-cell adhesion and specificity
eLife 5:e19058.
https://doi.org/10.7554/eLife.19058
