Molecular mechanism of cell-cell adhesion mediated by cadherin-23

Singaraju, G. S.; Kumar, A.; Samuel, J. S.; Sagar, A.; Hazra, J. P.; Sannigrahi, M. K.; Yennamalli, R. M.; Ashish, F. N. U.; Rakshit, S.

doi:10.1101/208272

bioRxiv · 10.1101/208272

Molecular mechanism of cell-cell adhesion mediated by cadherin-23

Singaraju, G. S.·Kumar, A.·Samuel, J. S.·Sagar, A.·Hazra, J. P.·Sannigrahi, M. K.·Yennamalli, R. M.·Ashish, F. N. U.·Rakshit, S.

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Abstract

Adherin-junctions are traditionally described by the homophilic-interactions of classical cadherin-proteins at the extracellular region. However, the role of long-chain non-classical cadherins like cadherin-23(Cdh23) is not explored as yet even though it is implicated in tissue-morphogenesis, cancer, and force-sensing in neuronal tissues. Here, we identified a novel antiparallel-binding interface of Cdh23 homodimer in solution by combining biophysical and computational methods, in-vitro cell-binding, and mutational modifications. The dimer consists of two electrostatic-based interfaces extended up to two terminal domains, atypical to classical-cadherins known so far, and forms the strongest interactions in cadherin-family as measured using single-molecule force-spectroscopy. We further identified single point-mutation, E78K, that completely disrupts this binding. Interestingly, the mutation, S77L, found in skin cancers falls within the binding interface of the antiparallel-dimer. Overall, we provide the molecular architecture of Cdh23 at the cell-cell junctions which are likely to have far-reaching applications in the fields of mechanobiology and cancer.

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Singaraju, G. S., Kumar, A., Samuel, J. S., Sagar, A., Hazra, J. P., Sannigrahi, M. K., Yennamalli, R. M., Ashish, F. N. U., Rakshit, S.. 2017-10-24. Molecular mechanism of cell-cell adhesion mediated by cadherin-23. https://doi.org/10.1101/208272

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