Molecular basis of sidekick-mediated cell-cell adhesion and specificity.
Kerry M GoodmanMasahito YamagataXiangshu JinSeetha MannepalliPhinikoula S KatsambaGöran AhlsénAlina P SergeevaBarry HonigJoshua R SanesLawrence ShapiroPublished in: eLife (2016)
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.
Keyphrases
- cell adhesion
- single cell
- cell therapy
- stem cells
- induced apoptosis
- spinal cord
- spinal cord injury
- cell death
- mesenchymal stem cells
- mass spectrometry
- drug delivery
- blood brain barrier
- endoplasmic reticulum stress
- drug induced
- diabetic retinopathy
- brain injury
- subarachnoid hemorrhage
- cancer therapy
- molecular dynamics simulations
- binding protein