nature20121206-8

来自美国哈佛大学医学院的科学家利用结构和生化测量手段,阐明了耳细胞感受传导的分子机制以及钙粘蛋白新的相互作用机制,而钙粘蛋白是涉及组织和器官形态发生、神经连接性以及肿瘤的一个大蛋白家族。

-2012年12月6日《自然》

中文翻译


【题目】内耳动力传导所必需的施加传送力的钙粘蛋白键的结构

【译文】听觉和平衡利用内耳内耳细胞以转化机械刺激物,形成电信号。来自声波或耳移动的机械力通过顶端链接、由两种非典型钙粘蛋白(原钙粘蛋白15和钙粘蛋白23)组成的细丝而被传送到耳细胞转导通路。这两种蛋白与遗传性耳聋,并与以钙离子依赖方式影响尖端到尖端的长胞外结构域相关。然而,这种复合物的分子结构还不清楚。本研究结合结晶技术、分子动力学模拟以及结合实验,以界定原钙粘附蛋白15-钙粘蛋白23键。我们发现一种独特的钙粘蛋白相互作用机制,其中每种蛋白的两种最多的氨基末端钙粘蛋白重复单位(胞外钙粘蛋白重复单位1和2)相互作用以形成一种重叠的、反向平行异源二聚体。模拟预测毛细胞内这种尖端-链接键足够强大以抵御外力。此外,当应答钙离子移除时,这种复合物变得不稳定了,这主要是因为无钙离子钙粘蛋白重复单位的增加。最后,我们利用结构和生化测量手段研究了耳聋性突变干扰尖端链接功能的分子机制。总之,我们的结果阐明了耳细胞感受传导的分子机制以及钙粘蛋白新的相互作用机制,而钙粘蛋白是涉及组织和器官形态发生、神经连接性以及肿瘤的一个大蛋白家族。

英文原稿


[Title]: Structure of a force-conveying cadherin bond essential for inner-ear mechanotransduction

[Authors]:Marcos Sotomayor,1 Wilhelm A. Weihofen,2, 3 Rachelle Gaudet2 & David P. Corey1

[Abstract]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 transduction channels by tip links, fine filaments formed by two atypical cadherins known as protocadherin 15 and cadherin 23. These two proteins are involved in inherited deafness and feature long extracellular domains that interact tip-to-tip in a Ca2+-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 Ca2+ removal owing to increased flexure of Ca2+-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.

原文地址

http://www.nature.com/nature/journal/v492/n7427/full/nature11590.html

 

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