Outside-in engineering of cadherin endocytosis using a conformation strengthening antibody
Abstract P-cadherin, a crucial cell-cell adhesion protein which is overexpressed in numerous malignant cancers, is a popular target for drug delivery antibodies. However, molecular guidelines for engineering antibodies that can be internalized upon binding to P-cadherin are unknown. Here, we use a c...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-01-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-56478-6 |
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| _version_ | 1832571507569590272 |
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| author | Bin Xie Shipeng Xu Sanjeevi Sivasankar |
| author_facet | Bin Xie Shipeng Xu Sanjeevi Sivasankar |
| author_sort | Bin Xie |
| collection | DOAJ |
| description | Abstract P-cadherin, a crucial cell-cell adhesion protein which is overexpressed in numerous malignant cancers, is a popular target for drug delivery antibodies. However, molecular guidelines for engineering antibodies that can be internalized upon binding to P-cadherin are unknown. Here, we use a combination of biophysical, biochemical, and cell biological methods to demonstrate that trapping the P-cadherin extracellular region in an X-dimer adhesive conformation triggers cadherin endocytosis via an outside-in signaling mechanism. We show that the anti-cancer drug delivery monoclonal antibody CQY684, traps P-cadherin in an X-dimer conformation and strengthens this adhesive structure. Formation of stable X-dimers results in the phosphorylation of p120-catenin, a suppressor of cadherin endocytosis. This triggers the dissociation of p120-catenin from the X-dimer cytoplasmic region, which increases P-cadherin turnover and targets the cadherin-antibody complex to the lysosome. Our results establish an outside-in signaling mechanism that provides fundamental insights into how cells regulate adhesion and that can be exploited by anti-cadherin antibodies for intracellular drug delivery. |
| format | Article |
| id | doaj-art-412391230bd34195a64c88980d80a9d1 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-412391230bd34195a64c88980d80a9d12025-02-02T12:32:09ZengNature PortfolioNature Communications2041-17232025-01-0116111410.1038/s41467-025-56478-6Outside-in engineering of cadherin endocytosis using a conformation strengthening antibodyBin Xie0Shipeng Xu1Sanjeevi Sivasankar2Biophysics Graduate Group, University of CaliforniaDepartment of Biomedical Engineering, University of CaliforniaBiophysics Graduate Group, University of CaliforniaAbstract P-cadherin, a crucial cell-cell adhesion protein which is overexpressed in numerous malignant cancers, is a popular target for drug delivery antibodies. However, molecular guidelines for engineering antibodies that can be internalized upon binding to P-cadherin are unknown. Here, we use a combination of biophysical, biochemical, and cell biological methods to demonstrate that trapping the P-cadherin extracellular region in an X-dimer adhesive conformation triggers cadherin endocytosis via an outside-in signaling mechanism. We show that the anti-cancer drug delivery monoclonal antibody CQY684, traps P-cadherin in an X-dimer conformation and strengthens this adhesive structure. Formation of stable X-dimers results in the phosphorylation of p120-catenin, a suppressor of cadherin endocytosis. This triggers the dissociation of p120-catenin from the X-dimer cytoplasmic region, which increases P-cadherin turnover and targets the cadherin-antibody complex to the lysosome. Our results establish an outside-in signaling mechanism that provides fundamental insights into how cells regulate adhesion and that can be exploited by anti-cadherin antibodies for intracellular drug delivery.https://doi.org/10.1038/s41467-025-56478-6 |
| spellingShingle | Bin Xie Shipeng Xu Sanjeevi Sivasankar Outside-in engineering of cadherin endocytosis using a conformation strengthening antibody Nature Communications |
| title | Outside-in engineering of cadherin endocytosis using a conformation strengthening antibody |
| title_full | Outside-in engineering of cadherin endocytosis using a conformation strengthening antibody |
| title_fullStr | Outside-in engineering of cadherin endocytosis using a conformation strengthening antibody |
| title_full_unstemmed | Outside-in engineering of cadherin endocytosis using a conformation strengthening antibody |
| title_short | Outside-in engineering of cadherin endocytosis using a conformation strengthening antibody |
| title_sort | outside in engineering of cadherin endocytosis using a conformation strengthening antibody |
| url | https://doi.org/10.1038/s41467-025-56478-6 |
| work_keys_str_mv | AT binxie outsideinengineeringofcadherinendocytosisusingaconformationstrengtheningantibody AT shipengxu outsideinengineeringofcadherinendocytosisusingaconformationstrengtheningantibody AT sanjeevisivasankar outsideinengineeringofcadherinendocytosisusingaconformationstrengtheningantibody |