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Researchers identify mechanistic principles for developing antibodies to improve cadherin adhesion
Future treatments for advanced cancer may work by sticking cancer cells in place and preventing them from spreading throughout the body. A new study by researchers at the University of California, Davis, and the University of Washington shows how an antibody strengthens bonds between cells. The work was published Aug. 3 in Proceedings of the National Academy of Sciences. The monoclonal antibody 19A11, developed by Professor Barry Gumbiner at the University of Washington and the Seattle Children's Research Institute, binds to E-cadherin, a protein that helps cells stick together, particularly in epithelial layers that line the skin, gut...
Researchers identify mechanistic principles for developing antibodies to improve cadherin adhesion
Future treatments for advanced cancer may work by sticking cancer cells in place and preventing them from spreading throughout the body. A new study by researchers at the University of California, Davis, and the University of Washington shows how an antibody strengthens bonds between cells. The work was published Aug. 3 in Proceedings of the National Academy of Sciences.
The monoclonal antibody 19A11, developed by Professor Barry Gumbiner at the University of Washington and the Seattle Children's Research Institute, binds to E-cadherin, a protein that helps cells stick together, particularly in epithelial layers that line the skin, intestines and other organs. Cadherins and other adhesion molecules are important for maintaining vascular structure and preventing cancer metastasis, and play a role in inflammation and related diseases such as Crohn's disease and inflammatory bowel disease.
Researchers have previously found that treatment with 19A11 can prevent the spread of lung cancer cells in mice.
Bin Xie, a graduate student in biophysics, Professor Sanjeevi Sivasankar, Department of Biomedical Engineering, and colleagues at UC Davis and Seattle conducted detailed studies of how 19A11 binds to E-cadherin. Using X-ray crystallography, they found that the antibody binds E-cadherin near the site where it binds to another E-cadherin molecule. Using a combination of simulations and atomic force microscopy, they showed that 19A11 has two binding modes, one of which increases the adhesive strength of E-cadherin. This increased adhesion comes from the formation of a type of chemical bond called a salt bridge between the molecules.
By better understanding how this antibody can increase stickiness between cells, researchers hope to find ways to develop even more effective treatments in the same way.
Other authors of the paper include: Andrew Priest of UC Davis; Allison Maker, Seattle Children’s Research Institute and University of Washington; David Dranow, Jenny Phan and Thomas Edwards, Seattle Structural Genomics Center for Infectious Disease and UCB Pharma; Bart Staker and Peter Myler, Seattle Structural Genomics Center for Infectious Disease and Seattle Children's Research Institute. The work was supported in part by grants from the NIH and utilized resources from the Advanced Photon Source, a U.S. Department of Energy (DOE) Office of Science User Facility operated by Argonne National Laboratory.
Source:
University of California – Davis
Reference:
Xie, B., et al. (2022) Molecular mechanism for strengthening E-cadherin adhesion using a monoclonal antibody. Proceedings of the National Academy of Sciences. doi.org/10.1073/pnas.2204473119.
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