Redefining the structure of tip-links in hair-cells

Tip-link, the gating-spring in hearing, modulates the mechanoelectrotransduction process and protects the hearing sensory machineries from overexcited auditory inputs. Tip-links are formed by two exceptionally long cadherins, cadherin-23 and protocadherin-15. It is proposed that both the cadherins first independently form cis-dimers through lateral interactions and finally, engage in trans-interactions to form the heterotetrameric assembly in tip-links. In fact, the molecular details of the protocadherin cis-dimers are well-understood. However, little structural and molecular details are known for independent cis-dimer of cadherin-23. Using photo-induced cross-linking of unmodified proteins in solution and on lipid-membranes, we observed no trace of cadherin-23 cis-dimers, rather we captured trans-homodimers of cadherin-23. We thus, redefine the tip-link structure where protocadherin-15 remains as cis-dimers, however, two individual cadherin-23 binds to protocadherin-15 cis-dimer for tip linking.