PT  - JOURNAL ARTICLE
AU  - Singaraju, G. S.
AU  - Kumar, A.
AU  - Samuel, J. S.
AU  - Sagar, A.
AU  - Hazra, J. P.
AU  - Sannigrahi, M. K.
AU  - Yennamalli, R. M.
AU  - Ashish
AU  - Rakshit, S.
TI  - Molecular mechanism of cell-cell adhesion mediated by cadherin-23
AID  - 10.1101/208272
DP  - 2017 Jan 01
TA  - bioRxiv
PG  - 208272
4099  - http://biorxiv.org/content/early/2017/10/24/208272.short
4100  - http://biorxiv.org/content/early/2017/10/24/208272.full
AB  - 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.