Homophilic and Heterophilic Interactions of Type II Cadherins Identify Specificity Groups Underlying Cell-Adhesive Behavior

Julia Brasch, Phinikoula S. Katsamba, Oliver J. Harrison, Göran Ahlsén, Regina B. Troyanovsky, Indrajyoti Indra, Anna Kaczynska, Benjamin Kaeser, Sergey Troyanovsky, Barry Honig*, Lawrence Shapiro

*Corresponding author for this work

Research output: Contribution to journalArticle

14 Scopus citations

Abstract

Type II cadherins are cell-cell adhesion proteins critical for tissue patterning and neuronal targeting but whose molecular binding code remains poorly understood. Here, we delineate binding preferences for type II cadherin cell-adhesive regions, revealing extensive heterophilic interactions between specific pairs, in addition to homophilic interactions. Three distinct specificity groups emerge from our analysis with members that share highly similar heterophilic binding patterns and favor binding to one another. Structures of adhesive fragments from each specificity group confirm near-identical dimer topology conserved throughout the family, allowing interface residues whose conservation corresponds to specificity preferences to be identified. We show that targeted mutation of these residues converts binding preferences between specificity groups in biophysical and co-culture assays. Our results provide a detailed understanding of the type II cadherin interaction map and a basis for defining their role in tissue patterning and for the emerging importance of their heterophilic interactions in neural connectivity. Type II cadherins are a family of vertebrate cell adhesion proteins expressed primarily in the CNS. Brasch et al. measure binding between adhesive fragments, revealing homophilic and extensive selective heterophilic binding with specificities that define groups of similar cadherins. Structures reveal common adhesive dimers, with residues governing cell-adhesive specificity.

Original languageEnglish (US)
Pages (from-to)1840-1852
Number of pages13
JournalCell reports
Volume23
Issue number6
DOIs
StatePublished - May 8 2018

Keywords

  • cadherin
  • cell adhesion
  • crystal structure
  • hemophilic specificity
  • heterophilic specificity
  • neural patterning
  • synaptic targeting

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Brasch, J., Katsamba, P. S., Harrison, O. J., Ahlsén, G., Troyanovsky, R. B., Indra, I., Kaczynska, A., Kaeser, B., Troyanovsky, S., Honig, B., & Shapiro, L. (2018). Homophilic and Heterophilic Interactions of Type II Cadherins Identify Specificity Groups Underlying Cell-Adhesive Behavior. Cell reports, 23(6), 1840-1852. https://doi.org/10.1016/j.celrep.2018.04.012