TY - JOUR
T1 - Mechanism of dimerization and structural features of human LI-cadherin
AU - Yui, Anna
AU - Caaveiro, Jose M.M.
AU - Kuroda, Daisuke
AU - Nakakido, Makoto
AU - Nagatoishi, Satoru
AU - Goda, Shuichiro
AU - Maruno, Takahiro
AU - Uchiyama, Susumu
AU - Tsumoto, Kouhei
N1 - Funding Information:
Funding and additional information—This work was funded by a Grant-in-Aid for Scientific Research (A) 16H02420 (to K. T.) and a Grant-in-Aid for Scientific Research (B) 20H02531 (to K. T.) from the Japan Society for the Promotion of Science, a Grant-in-Aid for Scientific Research on Innovative Areas 19H05760 and 19H05766 (to K. T.) from the Ministry of Education, Culture, Sports, Science and Technology, and a Grant-in-Aid for JSPS Fellows 18J22330 (to A. Y.) from the Japan Society for the Promotion of Science.
Publisher Copyright:
© 2021 THE AUTHORS. Published by Elsevier Inc on behalf of American Society for Biochemistry and Molecular Biology. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
PY - 2021/9/1
Y1 - 2021/9/1
N2 - Liver intestine (LI)-cadherin is a member of the cadherin superfamily, which encompasses a group of Ca2+-dependent cell-adhesion proteins. The expression of LI-cadherin 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, because the cell adhesion mechanism of LI-cadherin has remained unknown, rational design of therapeutic molecules targeting this cadherin has been hampered. Here, we have studied the homodimerization mechanism of LI-cadherin. We report the crystal structure of the LI-cadherin homodimer containing its first four extracellular cadherin repeats (EC1-4). The EC1-4 homodimer exhibited a unique architecture different from that of other cadherins reported so far, driven by the interactions between EC2 of one protein chain and EC4 of the second protein chain. The crystal structure also revealed that LI-cadherin possesses a noncanonical calcium ion-free linker between the EC2 and EC3 domains. Various biochemical techniques and molecular dynamics simulations were employed to elucidate the mechanism of homodimerization. We also showed that the formation of the homodimer observed in the crystal structure is necessary for LI-cadherin-dependent cell adhesion by performing cell aggregation assays. Taken together, our data provide structural insights necessary to advance the use of LI-cadherin as a target for imaging gastric cancer.
AB - Liver intestine (LI)-cadherin is a member of the cadherin superfamily, which encompasses a group of Ca2+-dependent cell-adhesion proteins. The expression of LI-cadherin 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, because the cell adhesion mechanism of LI-cadherin has remained unknown, rational design of therapeutic molecules targeting this cadherin has been hampered. Here, we have studied the homodimerization mechanism of LI-cadherin. We report the crystal structure of the LI-cadherin homodimer containing its first four extracellular cadherin repeats (EC1-4). The EC1-4 homodimer exhibited a unique architecture different from that of other cadherins reported so far, driven by the interactions between EC2 of one protein chain and EC4 of the second protein chain. The crystal structure also revealed that LI-cadherin possesses a noncanonical calcium ion-free linker between the EC2 and EC3 domains. Various biochemical techniques and molecular dynamics simulations were employed to elucidate the mechanism of homodimerization. We also showed that the formation of the homodimer observed in the crystal structure is necessary for LI-cadherin-dependent cell adhesion by performing cell aggregation assays. Taken together, our data provide structural insights necessary to advance the use of LI-cadherin as a target for imaging gastric cancer.
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U2 - 10.1016/j.jbc.2021.101054
DO - 10.1016/j.jbc.2021.101054
M3 - Article
C2 - 34364873
AN - SCOPUS:85114300883
VL - 297
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
SN - 0021-9258
IS - 3
M1 - 101054
ER -