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Structure of a force-conveying cadherin bond essential for inner-ear mechanotransduction

机译：内耳机械传导必不可少的力传递钙粘蛋白键的结构

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摘要

Hearing and balance use hair cells in the inner ear to transform mechanical stimuli into electrical signals. Mechanical force from sound waves or head movements is conveyed to hair-cell transduc-tion channels by tip links, fine filaments formed by two atypical cadherins known as protocadherin 15 and cadherin 23 (refs 4, 5). These two proteins are involved in inherited deafness and feature long extracellular domains that interact tip-to-tip in a Ca~(2+)-dependent manner. However, the molecular architecture of this complex is unknown. Here we combine crystallography, molecular dynamics simulations and binding experiments to characterize the protocadherin 15-cadherin 23 bond. We find a unique cadherin interaction mechanism, in which the two most amino-terminal cadherin repeats (extracellular cadherin repeats 1 and 2) of each protein interact to form an overlapped, antiparallel heterodimer. Simulations predict that this tip-link bond is mechanically strong enough to resist forces in hair cells. In addition, the complex is shown to become unstable in response to Ca~(2+) removal owing to increased flexure of Ca~(2+)-free cadherin repeats. Finally, we use structures and biochemical measurements to study the molecular mechanisms by which deafness mutations disrupt tip-link function. Overall, our results shed light on the molecular mechanics of hair-cell sensory transduction and on new interaction mechanisms for cadherins, a large protein family implicated in tissue and organ morphogenesis, neural connectivity and cancer.
机译：听力和平衡利用内耳中的毛细胞将机械刺激转换为电信号。声波或头部运动产生的机械力通过尖端连接件（由称为procadcadherin 15和cadherin 23的两个非典型cadherins形成的细丝）传递到毛细胞传导通道（参考文献4、5）。这两种蛋白都与遗传性耳聋有关，并具有长的细胞外结构域，它们以Ca〜（2+）依赖性方式与尖端相互作用。但是，这种复合物的分子结构尚不清楚。在这里，我们结合晶体学，分子动力学模拟和绑定实验来表征原钙粘蛋白15-钙黏着蛋白23键。我们发现一种独特的钙黏着蛋白相互作用机制，其中每种蛋白质的两个最氨基末端的钙黏着蛋白重复（细胞外钙黏着蛋白重复1和2）相互作用形成一个重叠的，反平行的异二聚体。模拟预测，这种尖端连接键的机械强度足以抵抗毛细胞中的力。此外，由于不含Ca〜（2+）的钙黏着蛋白重复序列​​的挠曲增加，复合物显示出对Ca〜（2+）的去除变得不稳定。最后，我们使用结构和生化测量来研究耳聋突变破坏尖端连接功能的分子机制。总体而言，我们的研究结果揭示了毛细胞感觉传导的分子机制以及钙黏着蛋白的新相互作用机制，钙黏着蛋白是与组织和器官形态发生，神经连接和癌症有关的一个大蛋白家族。

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  • 来源
    《Nature》 |2012年第7427期|128-132|共5页
  • 作者

    Marcos Sotomayor; Wilhelm A. Weihofen; Rachelle Gaudet; David P. Corey;

  • 作者单位

    Howard Hughes Medical Institute and Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02115, USA;

    Department of Molecular and Cellular Biology, Harvard University, Cambridge, Massachusetts 02138, USA,Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, USA;

    Department of Molecular and Cellular Biology, Harvard University, Cambridge, Massachusetts 02138, USA;

    Howard Hughes Medical Institute and Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02115, USA;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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