GIPC3, multifunctional myosin adaptor in mammalian auditory hair cells

GIPC3是Gα相互作用蛋白C末端家族中的一员，被认为是 听证。GIPC3的11个突变分布在其三个结构域中，导致遗传 常染色体隐性遗传性聋。然而，GIPC3在听觉中发挥作用的分子基础 这些人类突变导致听力损失的机制和系统尚不清楚。我们 最近确定了与原型受体结合的GIPC3的结构，并确定了 GIPC3激活及其与非常规MYO6结合的分子机制 在听觉毛细胞中表达的肌球蛋白，对听力是必不可少的。这些生化和 结构研究使我们能够预测已知的与耳聋相关的GIPC3突变对其 激活和MYO6结合。我们已经生成了两个新的鼠标模型，其中一个缺乏功能 GIPC3和另一个在Gipc3中有W301X点突变的人，对应于 人类中最严重的听觉表型。这项研究将探索GIPC3具有的核心假设 在听觉毛细胞中扮演双重角色。我们假设在立体纤毛中GIPC3参与了形状的形成 CDH23/Myosin-VIIa和CDH23/Myosin-VIIa与CDH23/Myosin-VIIa和CDH23/Myosin-VIIa相互作用的力学转导和毛束结构 肌球蛋白-XVA。在细胞体中，GIPC3对皮层周围顶端的内吞作用是必不可少的 由于其与肌球蛋白VI的相互作用而产生的无颈区。所有这些功能对于正常的听力都是至关重要的。 然而，在机械传递过程中决定静息张力的确切分子机制是不确定的。 听觉毛细胞束中立体纤毛的高度和直径的分级 仍然是个谜。同样，人们对分子机制甚至是蛋白的作用也知之甚少。 额叶周围无颈内吞作用在毛细胞中的作用。这项研究的预期结果是 揭示(A)与GIPC3缺乏有关的耳聋的确切机制和(B) GIPC3在毛细胞功能中的生理作用，特别是在毛发的机械转导、形成 束状构筑，无颈皮周处有内吞作用。解读GIPC3的功能 蛋白质及其已知突变是开发治疗方法的关键一步 和/或预防依赖GIPC3的耳聋和听力损失。

GIPC3, a member of Gα-Interacting Protein, C-terminus (GIPC) family, is known to be essential for hearing. Eleven mutations in GIPC3, spread throughout its three structural domains, cause inherited autosomal recessive hearing loss. However, the molecular basis for GIPC3 function in the auditory system and the mechanisms by which these human mutations result in hearing loss are unknown. We have recently determined the structure of GIPC3 bound to a prototypical receptor and determined the molecular mechanism of GIPC3 activation and its subsequent binding to MYO6, the unconventional myosin that is expressed in the auditory hair cells and is essential for hearing. These biochemical and structural studies allowed us to predict the effects of known deafness-related mutations in GIPC3 on its activation and MYO6 binding. We have generated two new mouse models, one that is lacking functional GIPC3 and another one with a W301X point mutation in Gipc3 that corresponds to a mutation with the most severe auditory phenotype in humans. This study will explore the central hypothesis that GIPC3 has a dual role in the auditory hair cells. We hypothesize that in stereocilia GIPC3 is involved in shaping mechanotransduction and hair bundle structure through its interactions with CDH23/myosin-VIIa and myosin-XVa, respectively. In the cell body, GIPC3 is essential for apical endocytosis at the pericuticular neckless region due to its interaction with myosin-VI. All these functions are crucial for normal hearing. However, the exact molecular mechanisms that determine the resting tension in the mechanotransduc- tion machinery as well as gradation of stereocilia heights and diameters in the auditory hair cell bundles are still enigmatic. Likewise, very little is known about molecular mechanisms and even the role of pericuticular neckless endocytosis in the hair cell function. The expected outcomes of this study are to uncover (a) the precise mechanism of deafness associated with GIPC3 deficiency and (b) the physiological role of GIPC3 in hair cell functions, especially in mechanotransduction, formation of the hair bundle architecture, and endocytosis at the pericuticular neckless. Deciphering the function of GIPC3 protein and its known mutations is a critical step towards the development of therapies for the treatment and/or prevention of GIPC3-dependent deafness and hearing loss.