Molecular basis of sidekick-mediated cell-cell adhesion and specificity
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 (viatransinteractions) and Sdk clustering in isolated cells (viacisinteractions). 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 betweencisandtransinteractions provides a novel mechanism to sharpen the specificity of cell-cell interactions.
- Publication Date:
- OSTI Identifier:
- Resource Type:
- Journal Article
- Resource Relation:
- Journal Name: eLife; Journal Volume: 5; Journal Issue: 09, 2016
- eLife Sciences Publications, Ltd.
- Research Org:
- Advanced Photon Source (APS), Argonne National Laboratory (ANL), Argonne, IL (US)
- Sponsoring Org:
- Country of Publication:
- United States