Elasticity of individual protocadherin 15 molecules implicates tip links as the gating springs for hearing
Elasticity of individual protocadherin 15 molecules implicates tip links as the gating springs for hearing
复制标题
DOI：
10.1073/pnas.1902163116
复制
发表时间：
2019-05-28
影响因子：
11.1
通讯作者：
Hudspeth, A. J.
中科院分区：
文献类型：
--
作者：
Bartsch, Tobias F.;Hengel, Felicitas E.;Hudspeth, A. J.
毛细胞是内耳的感觉受体，对来自声音和加速度的机械力做出反应。每个毛细胞的一个基本特征是一系列丝状尖端连接，由蛋白质原钙粘蛋白15（PCDH 15）和钙粘蛋白23（CDH 23）组成，其张力被认为直接控制细胞的转导通道。这些连接被认为太硬，不能代表将毛束位移转换为能够打开通道的力的门控弹簧，并且没有提出可以通过改变尖端连接刚度来适应不同受体器官和动物中不同频率敏感性的毛细胞的机制。因此，门控弹簧的身份和运作机制仍然是感觉神经科学的中心问题。使用高精度的光阱，我们表明，一个单独的单体PCDH 15作为一个熵弹簧，是软得多，比其单靠的刚度将建议。这种低硬度意味着蛋白质是控制毛细胞转导通道的门控弹簧的重要部分。尖端连杆的熵性质则允许通过调节其张力来进行刚度控制。我们发现，PCDH15分子在张力下是不稳定的，并表现出丰富多样的可逆展开事件，当Ca2+浓度降低到生理水平时，这些事件会增加。因此，尖端连接张力和Ca2+浓度可能是自然界调节门控弹簧机械性能的参数。
Hair cells, the sensory receptors of the inner ear, respond to mechanical forces originating from sounds and accelerations. 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), whose tension is thought to directly gate the cell's transduction channels. These links are considered far too stiff to represent the gating springs that convert hair bundle displacement into forces capable of opening the channels, 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. Consequently, the gating spring's 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 suggest. This low stiffness implies that the protein is a significant part of the gating spring that controls a hair cell's transduction channels. The tip link's 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. Therefore, tip link tension and Ca2+ concentration are likely parameters through which nature tunes a gating spring's mechanical properties.