Molecular basis of sidekick-mediated cell-cell adhesion and specificity
- Molecular basis of sidekick-mediated cell-cell adhesion and specificity
- Goodman, Kerry
Mannepalli, Seetha M.
Katsamba, Phinikoula S.
Sergeeva, Alina P.
Sanes, Joshua R.
Shapiro, Lawrence S.
- Biochemistry and Molecular Biophysics
Zuckerman Mind Brain Behavior Institute
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- 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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- Kerry Goodman, Masahito Yamagata, Xiangshu Jin, Seetha M. Mannepalli, Phinikoula S. Katsamba, Goran Ahlsen, Alina P. Sergeeva, Barry Honig, Joshua R. Sanes, Lawrence S. Shapiro, 2016, Molecular basis of sidekick-mediated cell-cell adhesion and specificity, Columbia University Academic Commons, https://doi.org/10.7916/D8G462RQ.