Molecular mechanism for strengthening E-cadherin adhesion using a monoclonal antibody

Xie, B.; Maker, A.; Priest, A. V.; Dranow, D. M.; Phan, J. N.; Edwards, T. E.; Staker, B.; Myler, P. J.; Gumbiner, B. M.; Sivasankar, S.

doi:10.1101/2022.03.06.483190

bioRxiv · 10.1101/2022.03.06.483190

Molecular mechanism for strengthening E-cadherin adhesion using a monoclonal antibody

Xie, B.·Maker, A.·Priest, A. V.·Dranow, D. M.·Phan, J. N.·Edwards, T. E.·Staker, B.·Myler, P. J.·Gumbiner, B. M.·Sivasankar, S.

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Abstract

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 {beta}-strand and its complimentary binding pocket. Our results identify mechanistic principles for engineering antibodies to enhance Ecad adhesion.

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Xie, B., Maker, A., Priest, A. V., Dranow, D. M., Phan, J. N., Edwards, T. E., Staker, B., Myler, P. J., Gumbiner, B. M., Sivasankar, S.. 2022-03-06. Molecular mechanism for strengthening E-cadherin adhesion using a monoclonal antibody. https://doi.org/10.1101/2022.03.06.483190

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