Department of Molecular and Cellular Biology, Harvard University, Cambridge, United States; Center for Brain Science, Harvard University, Cambridge, United States
Xiangshu Jin
Department of Biochemistry and Molecular Biophysics, Columbia University, New York, United States; Howard Hughes Medical Institute, Columbia University, New York, United States
Seetha Mannepalli
Department of Biochemistry and Molecular Biophysics, Columbia University, New York, United States
Phinikoula S Katsamba
Howard Hughes Medical Institute, Columbia University, New York, United States; Department of Systems Biology, Columbia University, New York, United States
Göran Ahlsén
Howard Hughes Medical Institute, Columbia University, New York, United States; Department of Systems Biology, Columbia University, New York, United States
Alina P Sergeeva
Howard Hughes Medical Institute, Columbia University, New York, United States; Department of Systems Biology, Columbia University, New York, United States
Department of Biochemistry and Molecular Biophysics, Columbia University, New York, United States; Howard Hughes Medical Institute, Columbia University, New York, United States; Department of Systems Biology, Columbia University, New York, United States; Department of Medicine, Columbia University, New York, United States; Zuckerman Mind Brain and Behavior Institute, Columbia University, New York, United States
Department of Molecular and Cellular Biology, Harvard University, Cambridge, United States; Center for Brain Science, Harvard University, Cambridge, United States
Department of Biochemistry and Molecular Biophysics, Columbia University, New York, United States; Department of Systems Biology, Columbia University, New York, United States; Zuckerman Mind Brain and Behavior Institute, Columbia University, New York, United States
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.
