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Mechanism of dimerization and structural features of human LI-cadherin
Liver intestine (LI)-cadherin is a member of the cadherin superfamily, which encompasses a group of Ca(2+)-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...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society for Biochemistry and Molecular Biology
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8427231/ https://www.ncbi.nlm.nih.gov/pubmed/34364873 http://dx.doi.org/10.1016/j.jbc.2021.101054 |
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author | Yui, Anna Caaveiro, Jose M.M. Kuroda, Daisuke Nakakido, Makoto Nagatoishi, Satoru Goda, Shuichiro Maruno, Takahiro Uchiyama, Susumu Tsumoto, Kouhei |
author_facet | Yui, Anna Caaveiro, Jose M.M. Kuroda, Daisuke Nakakido, Makoto Nagatoishi, Satoru Goda, Shuichiro Maruno, Takahiro Uchiyama, Susumu Tsumoto, Kouhei |
author_sort | Yui, Anna |
collection | PubMed |
description | Liver intestine (LI)-cadherin is a member of the cadherin superfamily, which encompasses a group of Ca(2+)-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. |
format | Online Article Text |
id | pubmed-8427231 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | American Society for Biochemistry and Molecular Biology |
record_format | MEDLINE/PubMed |
spelling | pubmed-84272312021-09-13 Mechanism of dimerization and structural features of human LI-cadherin Yui, Anna Caaveiro, Jose M.M. Kuroda, Daisuke Nakakido, Makoto Nagatoishi, Satoru Goda, Shuichiro Maruno, Takahiro Uchiyama, Susumu Tsumoto, Kouhei J Biol Chem Research Article Liver intestine (LI)-cadherin is a member of the cadherin superfamily, which encompasses a group of Ca(2+)-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. American Society for Biochemistry and Molecular Biology 2021-08-06 /pmc/articles/PMC8427231/ /pubmed/34364873 http://dx.doi.org/10.1016/j.jbc.2021.101054 Text en © 2021 The Authors https://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Research Article Yui, Anna Caaveiro, Jose M.M. Kuroda, Daisuke Nakakido, Makoto Nagatoishi, Satoru Goda, Shuichiro Maruno, Takahiro Uchiyama, Susumu Tsumoto, Kouhei Mechanism of dimerization and structural features of human LI-cadherin |
title | Mechanism of dimerization and structural features of human LI-cadherin |
title_full | Mechanism of dimerization and structural features of human LI-cadherin |
title_fullStr | Mechanism of dimerization and structural features of human LI-cadherin |
title_full_unstemmed | Mechanism of dimerization and structural features of human LI-cadherin |
title_short | Mechanism of dimerization and structural features of human LI-cadherin |
title_sort | mechanism of dimerization and structural features of human li-cadherin |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8427231/ https://www.ncbi.nlm.nih.gov/pubmed/34364873 http://dx.doi.org/10.1016/j.jbc.2021.101054 |
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