Department of Neurobiology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.
Program in Neuroscience, Harvard University, Cambridge, MA, USA.
Nat Commun. 2021 Feb 8;12(1):849. doi: 10.1038/s41467-021-21033-6.
The conversion of auditory and vestibular stimuli into electrical signals is initiated by force transmitted to a mechanotransduction channel through the tip link, a double stranded protein filament held together by two adhesion bonds in the middle. Although thought to form a relatively static structure, the dynamics of the tip-link connection has not been measured. Here, we biophysically characterize the strength of the tip-link connection at single-molecule resolution. We show that a single tip-link bond is more mechanically stable relative to classic cadherins, and our data indicate that the double stranded tip-link connection is stabilized by single strand rebinding facilitated by strong cis-dimerization domains. The measured lifetime of seconds suggests the tip-link is far more dynamic than previously thought. We also show how Ca alters tip-link lifetime through elastic modulation and reveal the mechanical phenotype of a hereditary deafness mutation. Together, these data show how the tip link is likely to function during mechanical stimuli.
听觉和前庭刺激转化为电信号是由力通过尖端连接传递到机械转导通道引发的，尖端连接是由中间两个附着键保持在一起的双链蛋白丝。尽管认为它形成了相对静态的结构，但尖端连接的动力学尚未被测量。在这里，我们在单分子分辨率下对尖端连接的强度进行了生物物理特性分析。我们表明，与经典钙黏蛋白相比，单个尖端连接键具有更高的机械稳定性，并且我们的数据表明，双链尖端连接通过由强顺式二聚化结构域促进的单链重结合来稳定。测量的秒级寿命表明，尖端连接比之前认为的更加动态。我们还展示了 Ca 如何通过弹性调制来改变尖端连接的寿命，并揭示了遗传性耳聋突变的机械表型。这些数据一起表明了在机械刺激期间尖端连接可能的工作方式。
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