期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2022
卷号：119
期号：32
DOI：10.1073/pnas.2204473119
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance
E-cadherin is an essential cell–cell adhesion protein that plays key roles in the formation and maintenance of epithelial tissue. Deficiencies in E-cadherin adhesion are associated with the metastasis of a number of highly invasive cancers. Recently, monoclonal antibodies with potential therapeutic applications have been developed that strengthen E-cadherin adhesion. Here, we resolve the molecular mechanisms that underlie the function of these antibodies. We show that the monoclonal antibody 19A11 binds to E-cadherin near its primary adhesive motif and strengthens adhesion by forming a key salt bridge that stabilizes the E-cadherin binding site. Our results identify mechanistic principles for engineering antibodies to enhance cadherin adhesion.
E-cadherin (Ecad) is an essential cell–cell adhesion protein with tumor suppression properties. The adhesive state of Ecad can be modified by the monoclonal antibody 19A11, which has potential applications in reducing cancer metastasis. Using X-ray crystallography, we determine the structure of 19A11 Fab bound to Ecad and show that the antibody binds to the first extracellular domain of Ecad near its primary adhesive motif: the strand–swap dimer interface. Molecular dynamics simulations and single-molecule atomic force microscopy demonstrate that 19A11 interacts with Ecad in two distinct modes: one that strengthens the strand–swap dimer and one that does not alter adhesion. We show that adhesion is strengthened by the formation of a salt bridge between 19A11 and Ecad, which in turn stabilizes the swapped β-strand and its complementary binding pocket. Our results identify mechanistic principles for engineering antibodies to enhance Ecad adhesion.
