The binding of DCC-P3 motif and FAK-FAT domain mediates the initial step of netrin-1/DCC signaling for axon attraction
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Xu, Shutong
Liu, Yiqiong
Liu, Ying
Meijers, Rob
Zhang, Yan
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https://doi.org/10.1038/s41421-017-0008-8Metadata
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Xu, Shutong, Yiqiong Liu, Xiaolong Li, Ying Liu, Rob Meijers, Yan Zhang, and Jia-huai Wang. 2018. “The binding of DCC-P3 motif and FAK-FAT domain mediates the initial step of netrin-1/DCC signaling for axon attraction.” Cell Discovery 4 (1): 8. doi:10.1038/s41421-017-0008-8. http://dx.doi.org/10.1038/s41421-017-0008-8.Abstract
Netrin-1 plays a key role in axon guidance through binding to its receptor, Deleted in Colorectal Cancer (DCC). The initial step of signaling inside the cell after netrin-1/DCC ligation is the binding of DCC cytoplasmic P3 motif to focal adhesion targeting (FAT) domain of focal adhesion kinase (FAK). Here we report the crystal structure of P3/FAT complex. The helical P3 peptide interacts with a helix-swapped FAT dimer in a 2:2 ratio. Dimeric FAT binding is P3-specific and stabilized by a calcium ion. Biochemical studies showed that DCC-P3 motif and calcium ion could facilitate FAT dimerization in solution. Axon guidance assays confirm that the DCC/FAK complex is essential for netrin-1-induced chemoattraction. We propose that netrin-1/DCC engagement creates a small cluster of P3/FAT for FAK recruitment close to the cell membrane, which exerts a concerted effect with PIP2 for FAK signaling. We also compare P3/FAT binding with paxillin/FAT binding and discuss their distinct recognition specificity on a common FAT domain for axon attraction versus integrin signaling, respectively.Other Sources
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5818605/pdf/Terms of Use
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