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

Elife. 2016 Sep 19;5:e19058. doi: 10.7554/eLife.19058.


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.

Keywords: biophysics; cell adhesion; crystal structure; homophilic specificity; mouse; neural patterning; neuroscience; structural biology; synaptic targeting.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, N.I.H., Extramural

MeSH terms

  • Cell Adhesion*
  • Crystallography, X-Ray
  • DNA Mutational Analysis
  • Immunoglobulin G / chemistry*
  • Immunoglobulin G / genetics
  • Immunoglobulin G / metabolism*
  • Membrane Proteins / chemistry*
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Models, Molecular
  • Mutagenesis, Site-Directed
  • Mutant Proteins / genetics
  • Mutant Proteins / metabolism
  • Neurons / physiology*
  • Protein Conformation
  • Protein Multimerization
  • Retina / physiology*


  • Immunoglobulin G
  • Membrane Proteins
  • Mutant Proteins
  • Sdk2 protein, mouse
  • sidekick-1 protein, mouse