Redefining the Structure of Tip Links in Hair Cells

Tip links are seen under microscopesas double-helicaltetramericcomplexes of long nonclassical cadherins, cadherin-23 and protocadherin-15.The twisted filamentous structure enables tip links to regulate mechanotransductionin hearing and balance. While the molecular details of the double-helicalprotocadherin-15 cis dimers have been deciphered,a similar conformation of cadherin-23 is still elusive. In a searchof cadherin-23 cis dimers, we performed photoinducedcross-linking of unmodified proteins in solution and on lipid membranesand observed no trace of cadherin-23 cis dimers.Reportedly, tip links are dynamic connections, assembling and disassemblingin seconds. Using lipid vesicles, we measured significantly sloweraggregations between cis dimers of tip link cadherinsthan via dimer-monomer interactions, indicating that the trans interactions between two cis dimersmay possess steric restraints and defer reassociations. Reconnectionsof tip links are thus kinetically most desired between protocadherin-15 cis dimers and cadherin-23 monomers. Here we propose thatthe helical geometry of tip links is induced by protocadherin-15 cis dimers, while cadherin-23 remains single before tiplinking.