Regulation of multiple dimeric states of E-cadherin by adhesion activating antibodies revealed through Cryo-EM and X-ray crystallography

Maker, A.; Bolejack, M.; Schecterson, L.; Hammerson, B.; Abendroth, J.; Edwards, T. E.; Staker, B.; Myler, P. J.; Gumbiner, B. M.

doi:10.1101/2022.03.21.484361

bioRxiv · 10.1101/2022.03.21.484361

Regulation of multiple dimeric states of E-cadherin by adhesion activating antibodies revealed through Cryo-EM and X-ray crystallography

Maker, A.·Bolejack, M.·Schecterson, L.·Hammerson, B.·Abendroth, J.·Edwards, T. E.·Staker, B.·Myler, P. J.·Gumbiner, B. M.

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Abstract

E-cadherin adhesion is regulated at the cell surface, a process that can be replicated by activating antibodies. We use cryo-EM and X-ray crystallography to examine functional states of the cadherin adhesive dimer. This dimer is mediated by N-terminal beta strand-swapping involving Trp2, and forms via a different transient X-dimer intermediate. X-dimers are observed in cryo-EM along with monomers and strand-swap dimers, indicating that X-dimers form stable interactions. A novel EC4-mediated dimer was also observed. Activating Fab binding caused no gross structural changes in E- cadherin monomers but can facilitate strand swapping. Moreover, activating Fab binding is incompatible with the formation of the X-dimer. Both cryo-EM and X-ray crystallography reveal a distinctive twisted strand-swap dimer conformation caused by an outward shift in the N-terminal beta strand that may represent a strengthened state. Thus, regulation of adhesion involves changes in cadherin dimer configurations.

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Maker, A., Bolejack, M., Schecterson, L., Hammerson, B., Abendroth, J., Edwards, T. E., Staker, B., Myler, P. J., Gumbiner, B. M.. 2022-03-22. Regulation of multiple dimeric states of E-cadherin by adhesion activating antibodies revealed through Cryo-EM and X-ray crystallography. https://doi.org/10.1101/2022.03.21.484361

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