A double S shape provides the structural basis for the extraordinary binding specificity of Dscam isoforms

TitleA double S shape provides the structural basis for the extraordinary binding specificity of Dscam isoforms
Publication TypeJournal Article
Year of Publication2008
AuthorsSawaya, M. R., Wojtowicz W. M., Andre I., Qian B., Wu W., Baker D., Eisenberg D., & Zipursky L. S.
JournalCell
Volume134
Issue6
Pagination1007-18
Date Published2008 Sep 19
ISSN1097-4172
KeywordsAnimals, Binding Sites, Cell Adhesion Molecules, Collaborative Publication, Crystallography, X-Ray, Drosophila melanogaster, Drosophila Proteins, Immunoglobulins, Models, Molecular, Protein Folding, Protein Isoforms, Protein Structure, Quaternary, Protein Structure, Tertiary
Abstract

Drosophila Dscam encodes a vast family of immunoglobulin (Ig)-containing proteins that exhibit isoform-specific homophilic binding. This diversity is essential for cell recognition events required for wiring the brain. Each isoform binds to itself but rarely to other isoforms. Specificity is determined by "matching" of three variable Ig domains within an approximately 220 kD ectodomain. Here, we present the structure of the homophilic binding region of Dscam, comprising the eight N-terminal Ig domains (Dscam(1-8)). Dscam(1-8) forms a symmetric homodimer of S-shaped molecules. This conformation, comprising two reverse turns, allows each pair of the three variable domains to "match" in an antiparallel fashion. Structural, genetic, and biochemical studies demonstrate that, in addition to variable domain "matching," intramolecular interactions between constant domains promote homophilic binding. These studies provide insight into how "matching" at all three pairs of variable domains in Dscam mediates isoform-specific recognition.

Alternate JournalCell
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