1. Department of Medical Oncology and,
2. Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA
3. Department of Medicine,
4. Department of Neurobiology,
5. Department of Cell Biology,
6. Department of Pediatrics and,
7. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, USA
8. Institute for Biology III, University of Freiburg, D-79104 Freiburg im Breisgau, Germany
9. These authors contributed equally to this work.
10. Present address: Synchrotron Soleil, L'Orme des Merisiers, 91192 Saint Aubin, France.

Correspondence to: Jia-huai Wang^1,6,7Dietmar Schmucker^2,4 Correspondence and requests for materials should be addressed to J.-h.W. (Email: jwang@red.dfci.harvard.edu) and D.S. (Email: dietmar_schmucker@dfci.harvard.edu).

The Dscam gene gives rise to thousands of diverse cell surface receptors¹ thought to provide homophilic and heterophilic recognition specificity for neuronal wiring^{2, 3, 4} and immune responses⁵. Mutually exclusive splicing allows for the generation of sequence variability in three immunoglobulin ecto-domains, D2, D3 and D7. We report X-ray structures of the amino-terminal four immunoglobulin domains (D1–D4) of two distinct Dscam isoforms. The structures reveal a horseshoe configuration, with variable residues of D2 and D3 constituting two independent surface epitopes on either side of the receptor. Both isoforms engage in homo-dimerization coupling variable domain D2 with D2, and D3 with D3. These interactions involve symmetric, antiparallel pairing of identical peptide segments from epitope I that are unique to each isoform. Structure-guided mutagenesis and swapping of peptide segments confirm that epitope I, but not epitope II, confers homophilic binding specificity of full-length Dscam receptors. Phylogenetic analysis shows strong selection of matching peptide sequences only for epitope I. We propose that peptide complementarity of variable residues in epitope I of Dscam is essential for homophilic binding specificity.

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