Molecular Mechanism of the Strong Cell-Adhesion by Cadherin-23
66 Pages Posted: 11 Apr 2018 Sneak Peek Status: Review CompleteMore...
Cadherin-23, a giant non-classical cadherin, has a stronger cell-aggregating index compared to classical E-cadherin and possesses the ability to sort cells on the basis of the classes of cadherins. These phenomena overall indicated a different antiparallel-binding interface of the Cadherin-23 homodimer from classical-cadherins. Combining biochemical, biophysical, and computational methodologies, we generated a model of the homodimer, and confirmed by mutational modifications. The dimer consists of two electrostatic-based interfaces extended up to two terminal domains. This is atypical to classical-cadherins, and favors high cell-aggregating propensity. We quantified the strength of the dimer using single-molecule force spectroscopy, and measured significantly low off-rate(~8x10-4s-1). We identified a point-mutation, E78K, that disrupts this binding. Interestingly similar mutation at the binding interface was identified in skin-cancer, supporting the physiological relevance of the interface. Overall, this novel structural basis of the strong Cadherin-23 adhesion may have far-reaching applications in the fields of mechanobiology and cancer.
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