N-terminal horseshoe conformation of DCC is functionally required for axon guidance and might be shared by other neural receptors.
Publication Type:Journal Article
Source:J Cell Sci, Volume 126, Issue Pt 1, p.186-95 (2013)
Keywords:Animals, Axons, Cells, Cultured, Chromatography, Gel, Crystallography, X-Ray, DCC Receptor, Embryo, Mammalian, Immunohistochemistry, Immunoprecipitation, Mice, Mice, Knockout, Molecular Weight, Protein Structure, Tertiary, Receptors, Cell Surface, Sensory Receptor Cells, Tumor Suppressor Proteins
<p>Deleted in colorectal cancer (DCC) is a receptor for the 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. In the present study, we reveal 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, nearly all of which function in the nervous system. The N-terminal horseshoe appears to be evolutionally selected as a platform for neural receptors.</p>