PT  - JOURNAL ARTICLE
AU  - G. S. Singaraju
AU  - A. Kumar
AU  - J. S. Samuel
AU  - A. Sagar
AU  - J. P. Hazra
AU  - M. K. Sannigrahi
AU  - R. M. Yennamalli
AU  - Ashish
AU  - S. Rakshit
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.