title: N-terminal horseshoe conformation of DCC is functionally required for axon guidance and might be shared by other neural receptors.
abstract: 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.
authors.affiliation: Department of Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Chen
authors.forename: Xiaqin
authors.initials: X
authors.lastname: Sun
authors.forename: Xiao-hong
authors.initials: XH
authors.lastname: Zhou
authors.forename: Jin-huan
authors.initials: JH
authors.lastname: Liu
authors.forename: Jane
authors.initials: J
authors.lastname: Wu
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Jia-huai
authors.initials: JH
authors.lastname: Wang
mesh_terms: D000818:Animals; D001369:Axons; D002478:Cells, Cultured; D002850:Chromatography, Gel; D018360:Crystallography, X-Ray; D000075389:DCC Receptor; D004622:Embryo, Mammalian / Q000166:cytology; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D051379:Mice; D018345:Mice, Knockout; D008970:Molecular Weight; D017434:Protein Structure, Tertiary; D011956:Receptors, Cell Surface / Q000737:chemistry* / Q000378:metabolism*; D011984:Sensory Receptor Cells / Q000737:chemistry / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D000075389:DCC Receptor; C501912:Dcc protein, rat; D011956:Receptors, Cell Surface; D025521:Tumor Suppressor Proteins