Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.09.18.291195v1?rss=1 Authors: Yui, A., Caaveiro, J. M. M., Kuroda, D., Nakakido, M., Nagatoishi, S., Goda, S., Maruno, T., Uchiyama, S., Tsumoto, K. Abstract: LI-cadherin is a member of cadherin superfamily which is a Ca2+-dependent cell adhesion protein. Its expression is observed on various types of cells in the human body such as normal small intestine and colon cells, and gastric cancer cells. Because its expression is not observed on normal gastric cells, LI-cadherin is a promising target for gastric cancer imaging. However, since the cell adhesion mechanism of LI-cadherin has remained unknown, rational design of therapeutics targeting this cadherin has been complicated. Here, we have studied the homodimerization mechanism of LI-cadherin. We report the crystal structure of the LI-cadherin EC1-4 homodimer. The EC1-4 homodimer exhibited a unique architecture different from that of other cadherins reported so far. The crystal structure also revealed that LI-cadherin possesses a noncanonical calcium ion-free linker between EC2 and EC3. We also show that LI-cadherin EC1-2 and EC3-4 have different characteristics to that of the EC1-2 domains of classical cadherins despite the sequence similarity among them. Various biochemical techniques, molecular dynamics (MD) simulations and small angle X-ray scattering (SAXS) were employed to elucidate the mechanism of homodimerization. We expect these findings will advance the generation of therapeutic molecules targeting LI-cadherin and to establish the specific role of LI-cadherin on cancer cells. Copy rights belong to original authors. Visit the link for more info