Hair-Bundle Links: Genetics as the Gateway to Function
Hair-Bundle Links: Genetics as the Gateway to Function
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DOI：
10.1101/cshperspect.a033142
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发表时间：
2019-12-01
影响因子：
5.4
通讯作者：
Petit, Christine
中科院分区：
文献类型：
--
作者：
Richardson, Guy P.;Petit, Christine
在一些物种中，最多有五种不同的细胞表面专化连接成熟毛束的立纤毛和动纤毛：动纤毛连接、顶端连接、顶端连接、干连接和脚踝连接。在发育发束的过程中，瞬间的侧向连接是突出的。与这些链接相关的编码蛋白质的基因突变会导致Usher耳聋/失明综合症或非综合征(孤立)形式的人类遗传性耳聋，而拥有这些基因的结构性或条件性等位基因的小鼠已经对不同链接的分子组成和功能提供了相当大的洞察力。我们描述了这些链接的结构，并回顾了证据表明CDH23和PCDH15是顶端、动丝和瞬时-侧向链接的组成部分，立体素(STRC)和蛋白酪氨酸磷酸酶(PTPRQ)分别与顶部和骨干连接器相关，USH2A和ADGRV1与脚踝链接相关。虽然末端连接是机电转导所必需的，但所有连接蛋白在毛束的正常发育和/或维持结构和功能中起着关键作用。最近对PCDH15和CDH23的结晶学和单粒子分析提供了关于尖端连接的结构如何有助于预测与毛细胞的机电换能器通道串联的弹性元件的洞察。
Up to five distinct cell-surface specializations interconnect the stereocilia and the kinocilium of the mature hair bundle in some species: kinocilial links, tip links, top connectors, shaft connectors, and ankle links. In developing hair bundles, transient lateral links are prominent. Mutations in genes encoding proteins associated with these links cause Usher deafness/blindness syndrome or nonsyndromic (isolated) forms of human hereditary deafness, and mice with constitutive or conditional alleles of these genes have provided considerable insight into the molecular composition and function of the different links. We describe the structure of these links and review evidence showing CDH23 and PCDH15 are components of the tip, kinocilial, and transient-lateral links, that stereocilin (STRC) and protein tyrosine phosphatase (PTPRQ) are associated with top and shaft connectors, respectively, and that USH2A and ADGRV1 are associated with the ankle links. Whereas tip links are required for mechanoelectrical transduction, all link proteins play key roles in the normal development and/or the maintenance of hair bundle structure and function. Recent crystallographic and single-particle analyses of PCDH15 and CDH23 provide insight as to how the structure of tip link may contribute to the elastic element predicted to lie in series with the hair cell's mechanoelectrical transducer channel.