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J Cell Sci. 2013 Jan 1;126(Pt 1):186-95. doi: 10.1242/jcs.111278. Epub 2012 Oct 4.

N-terminal horseshoe conformation of DCC is functionally required for axon guidance and might be shared by other neural receptors.

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Department of Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.


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.

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