The elasticity of individual protocadherin 15 molecules implicates cadherins as the gating springs for hearing

Abstract

Hair cells, the sensory receptors of the inner ear, respond to mechanical forces originating from sounds and accelerations1,2. An essential feature of each hair cell is an array of filamentous tip links, consisting of the proteins protocadherin 15 (PCDH15) and cadherin 23 (CDH23)3, whose tension is thought to directly gate the cells transduction channels4,5,6. These links are considered far too stiff to represent the gating springs that convert hair-bundle displacement into forces capable of opening the channels7,8, and no mechanism has been suggested through which tip-link stiffness could be varied to accommodate hair cells of distinct frequency sensitivity in different receptor organs and animals. As a consequence, the gating springs identity and mechanism of operation remain central questions in sensory neuroscience. Using a high-precision optical trap, we show that an individual monomer of PCDH15 acts as an entropic spring that is much softer than its enthalpic stiffness alone would suggest7,8. This low stiffness implies that the protein is a significant part of the gating spring that controls a hair cells transduction channels. The tip links entropic nature then allows for stiffness control through modulation of its tension. We find that a PCDH15 molecule is unstable under tension and exhibits a rich variety of reversible unfolding events that are augmented when the Ca2+ concentration is reduced to physiological levels. Tip-link tension and Ca2+ concentration are therefore likely parameters through which nature tunes a gating springs mechanical properties.