Tip-links serve as force-pass filter to fulfil the role of gating-springs

Abstract

Tip-links as gating-spring in the mechanotransduction in hearing is still a debate. While the molecular elasticity of individual tip-link proteins warrants its candidature, the apparent rigidity from the heterotetrameric tip-links assembly refutes the claim. Using force-clamp experiments and simulations, we report that the heterotetrameric assembly is the natural selection for the gating-springs. Tip-links follow slip-ideal-slip bonds with increasing force. While in slip, the complex dissociates monotonously, ideal-bond interface responds indifferently to various auditory inputs. Insensitivity to forces renders tip-links as low-force pass filter, characteristic of gating-spring. Individual tip-links, however, forms slip-catch-slip bonds under tension. While catch bonds turn stronger with force from loud sound, our Langevin dynamics indicated the transition from slip-catch to slip-ideal bonds as cooperative effect of the dimers of individual protein complexes in tip-links. From molecular dynamics, we deciphered the molecular mechanism of catch bonds and its importance in deafness.

Redefining the structure of tip-links in hair-cells

“…Tip-links in response conveys a threshold force to the MET channel for opening and thus, convert the mechanical input into an electrical signal 5,6 . Tip-links in this process of mechanotransduction serve as low-force pass-filter as gating-spring which transduce a small force from auditory inputs and filter overexcitation to protect the sensory machineries 7 . Tip-links are made up of two long non-classical cadherins, cadherin-23 (Cdh23) and protocadherin-15 (Pcdh15) 8,9 .…”