Abstract
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.
Highlights
Transmembrane domain, and a short cytoplasmic domain [3]
EC1-5 and EC3-7 expressing cells did not show aggregation ability even when they were mixed in equal amounts (Fig. S12). This result excluded the possibility of nonsymmetrical interaction of the extracellular cadherin (EC) repeats (e.g., EC1-2 and EC3-4, EC1-2 and EC6-7, etc.). This is the first report examining the architecture of LIcadherin EC1-4 homodimer and the flexibility of the Ca2+free linker in Liver intestine (LI)-cadherin
The mutational study and the cell aggregation assay showed that LI-cadherin–dependent cell adhesion is mediated by the formation of the dimerization interface between EC2 in one chain and EC4 in the other chain, and the contribution from other EC repeats
Summary
Transmembrane domain, and a short cytoplasmic domain [3]. Previous studies have reported the expression of LI-cadherin on various types of cells, such as normal intestine cells, intestinal metaplasia, colorectal cancer cells, and lymph node metastatic gastric cancer cells [4, 5]. Previous studies have reported that LI-cadherin works as a calcium ion–dependent cell adhesion molecule as other cadherins do [7]. LI-cadherin is different from classical cadherins in several aspects, such as the number of EC repeats and the length and sequence of the cytoplasmic domain. The crystal structure revealed a dimerization architecture different from that of any other cadherin reported so far. It showed canonical calcium-binding motifs between EC1 and EC2, and between EC3 and EC4, but not between EC2 and EC3. Our study revealed possible architectures of LI-cadherin homodimers at the cell surface and suggested the differential role of the two additional EC repeats at the Nterminus compared with classical cadherins
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