[Show abstract][Hide abstract] ABSTRACT: Dscam (Down Syndrome Cell Adhesion Molecule), a member of immunoglobulin superfamily (IgSF), is a receptor for netrin-1 [1,2], a classical axon guidance cue. The interaction between netrin-1 and Dscam plays an important role in the development of the nervous system. Here, we present the crystal structure of the N-terminal four Ig-like domains of Dscam. The molecule folds into a horseshoe-like configuration. A comparison of this Dscam horseshoe with the previously described horseshoe structures of other cell-surface receptors has revealed fascinating conserved structural features and important sequence markers for these IgSF proteins. This discovery can help us predict the horseshoe configuration N-terminal arrangements in a number of other structurally unknown neural receptors. The N-terminal horseshoe has been shown to be engaged in homophilic and heterophilic interactions between two cell-surface receptors.
Preview · Article · Aug 2014 · Acta Crystallographica Section A: Foundations and Advances
[Show abstract][Hide abstract] ABSTRACT: DCC (Deleted in Colorectal Cancer) is a receptor for axon guidance cues netrin-1 and draxin. The interactions between these guidance cues and DCC play a key role in the development of the nervous system. Here, we present the crystal structure of the N-terminal four Ig-like domains of DCC. The molecule folds into a horseshoe-like configuration. We demonstrate that this horseshoe conformation of DCC is required for guidance cue mediated axonal attraction. Structure-based mutations that disrupt the DCC horseshoe indeed impair its function. A comparison of the DCC horseshoe with previously described horseshoe structures has revealed striking conserved structural features and important sequence signatures. Using these signatures a genome-wide search allows us to predict the N-terminal horseshoe arrangement in a number of other cell surface receptors, which nearly all function in the nervous system. The N-terminal horseshoe appears to be evolutionally selected as a platform for neural receptors.
Full-text · Article · Oct 2012 · Journal of Cell Science
[Show abstract][Hide abstract] ABSTRACT: Developmental endothelial cell locus-1 (Del-1) glycoprotein is secreted by endothelial cells and a subset of macrophages. Del-1 plays a regulatory role in vascular remodeling and functions in innate immunity through interaction with integrin α(V)β(3). Del-1 contains 3 epidermal growth factor (EGF)-like repeats and 2 discoidin-like domains. An Arg-Gly-Asp (RGD) motif in the second EGF domain (EGF2) mediates adhesion by endothelial cells and phagocytes. We report the crystal structure of its 3 EGF domains. The RGD motif of EGF2 forms a type II' β turn at the tip of a long protruding loop, dubbed the RGD finger. Whereas EGF2 and EGF3 constitute a rigid rod via an interdomain calcium ion binding site, the long linker between EGF1 and EGF2 lends considerable flexibility to EGF1. Two unique O-linked glycans and 1 N-linked glycan locate to the opposite side of EGF2 from the RGD motif. These structural features favor integrin binding of the RGD finger. Mutagenesis data confirm the importance of having the RGD motif at the tip of the RGD finger. A database search for EGF domain sequences shows that this RGD finger is likely an evolutionary insertion and unique to the EGF domain of Del-1 and its homologue milk fat globule-EGF 8.
Full-text · Article · May 2012 · The FASEB Journal
[Show abstract][Hide abstract] ABSTRACT: The αβ T cell receptor (TCR) is a multimeric complex whose β chain plays a crucial role in thymocyte development as well as antigen recognition by mature T lymphocytes. We report here crystal structures of individual β subunits, termed N15β (Vβ5.2Dβ2Jβ2.6Cβ2) and N30β (Vβ13Dβ1Jβ1.1Cβ2), derived from two αβ TCRs specific for the immunodominant vesicular stomatitis virus octapeptide (VSV-8) bound to the murine H-2K(b) MHC class I molecule. The crystal packing of the N15β structure reveals a homodimer formed through two Vβ domains. The Vβ/Vβ module is topologically very similar to the Vα/Vβ module in the N15αβ heterodimer. By contrast, in the N30β structure, the Vβ domain's external hydrophobic CFG face is covered by the neighboring molecule's Cβ domain. In conjunction with systematic investigation of previously published TCR single-subunit structures, we identified several conserved residues forming a concave hydrophobic patch at the center of the CFG outer face of the Vβ and other V-type Ig-like domains. This hydrophobic patch is shielded from solvent exposure in the crystal packing, implying that it is unlikely to be thermodynamically stable if exposed on the thymocyte surface. Accordingly, we propose a dimeric pre-TCR model distinct from those suggested previously by others and discuss its functional and structural implications.
Full-text · Article · Mar 2011 · Frontiers in Immunology