An elastic element in the protocadherin-15 tip link of the inner ear.
An elastic element in the protocadherin-15 tip link of the inner ear.
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DOI：
10.1038/ncomms13458
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发表时间：
2016-11-18
影响因子：
16.6
通讯作者：
Sotomayor, Marcos
中科院分区：
文献类型：
--
作者：
Araya-Secchi, Raul;Neel, Brandon L.;Sotomayor, Marcos
尖端连接丝传递力量和门内耳毛细胞转导通道，以调节对声音和头部运动的感知。钙粘蛋白-23和原钙粘蛋白-15通过钙依赖的相互作用形成末端连接，其胞外区由多个胞外钙粘蛋白(EC)重复组成。这些重复序列在结构上相似，但在序列上不完全相同，通常以具有保守的钙结合位点的连接子为特征，赋予它们机械强度。在这里，我们介绍了人原钙粘蛋白-15 EC8-EC10和小鼠EC9-EC10的X射线晶体结构，其中显示了EC8-9典型的钙结合连接子和EC9-10的无钙连接子，它改变了EC重复序列的线性排列。分子动力学模拟和小角X射线散射实验支持这种非线性构象。模拟还表明，EC9-10的不弯曲为原本刚性的尖端连杆提供了一些弹性。这一新结构首次揭示了原钙粘蛋白-15‘S的非典型EC连接子，并暗示了它们如何在内耳机械转导中发挥作用，以及对其他钙粘附素的影响。尖端的细丝传递力量来激活毛细胞，毛细胞是重要的感官受体。在这里，作者解决了人类Protocadherin-15的部分结构，这是一种尖端连接组件，具有不寻常的无钙连接物，可以弯曲，并被预测在内耳机械转导过程中赋予这种细丝灵活性。
Tip link filaments convey force and gate inner-ear hair-cell transduction channels to mediate perception of sound and head movements. Cadherin-23 and protocadherin-15 form tip links through a calcium-dependent interaction of their extracellular domains made of multiple extracellular cadherin (EC) repeats. These repeats are structurally similar, but not identical in sequence, often featuring linkers with conserved calcium-binding sites that confer mechanical strength to them. Here we present the X-ray crystal structures of human protocadherin-15 EC8–EC10 and mouse EC9–EC10, which show an EC8–9 canonical-like calcium-binding linker, and an EC9–10 calcium-free linker that alters the linear arrangement of EC repeats. Molecular dynamics simulations and small-angle X-ray scattering experiments support this non-linear conformation. Simulations also suggest that unbending of EC9–10 confers some elasticity to otherwise rigid tip links. The new structure provides a first view of protocadherin-15's non-canonical EC linkers and suggests how they may function in inner-ear mechanotransduction, with implications for other cadherins. Tip-link filaments convey force to activate hair cells, important sensory receptors. Here the authors solve a partial structure of human protocadherin-15, a tip-link component with an unusual Ca2+–free linker that bends and is predicted to confer flexibility to this filament during inner-ear mechanotransduction.
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影响因子：
19
作者：
Brasch J;Harrison OJ;Honig B;Shapiro L
通讯作者：
Shapiro L
DOI：
10.1007/978-1-62703-691-7_18
发表时间：
2014
期刊：
Methods in molecular biology (Clifton, N.J.)
影响因子：
--
作者：
Dyer, Kevin N;Hammel, Michal;Rambo, Robert P;Tsutakawa, Susan E;Rodic, Ivan;Classen, Scott;Tainer, John A;Hura, Greg L
通讯作者：
Hura, Greg L
影响因子：
64.5
作者：
Gillespie PG;Müller U
通讯作者：
Müller U
DOI：
10.1073/pnas.1006284107
发表时间：
2010-06-08
影响因子：
11.1
作者：
Elledge, Heather M.;Kazmierczak, Piotr;Mueller, Ulrich
通讯作者：
Mueller, Ulrich
影响因子：
3.5
作者：
Alagramam, KN;Yuan, HJ;Smith, RJH
通讯作者：
Smith, RJH