Molecular basis of sidekick-mediated cell-cell adhesion and specificity.

Kerry M Goodman,Xiangshu Jin,Phinikoula S Katsamba,Alina P Sergeeva,Joshua R Sanes,Lawrence Shapiro,Seetha Mannepalli,Barry Honig,Masahito Yamagata,Göran Ahlsén

doi:10.7554/elife.19058

Kerry M Goodman, Xiangshu Jin + Show 8 more

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https://doi.org/10.7554/elife.19058

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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.

Highlights

In the vertebrate retina, light-sensitive photoreceptors synapse on interneurons; these interneurons process the information and pass it to retinal ganglion cells (RGCs), which send it to the brain (Masland, 2012)
The cell adhesion molecules Sdk1 and Sdk2, like Dscams and CNTNs, provide molecular cues that determine the specificity of particular synaptic connections in the retina (Yamagata and Sanes, 2008)
We have presented multiple crystal structures of the Sdk1 and Sdk2 Ig-domain mediated homodimers that are required for Sdk-mediated cell-cell adhesion

Summary

Introduction

Light-sensitive photoreceptors synapse on interneurons; these interneurons process the information and pass it to retinal ganglion cells (RGCs), which send it to the brain (Masland, 2012). Stereotyped patterns of connectivity between the ~70 types of interneurons and ~30 types of RGCs render the latter sensitive to specific visual features such as motion or edges (Sanes and Masland, 2015) Synapses between these interneurons and RGCs form in the inner plexiform layer (IPL) of the retina, with arbors of each specific neuronal subtype confined to one, or a few, of the approximately 10 sublaminae (Roska and Werblin, 2001; Sanes and Zipursky, 2010). Some aspects of this specific connectivity appear to be mediated by recognition molecules of the immunoglobulin superfamily (IgSF).

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