GIPC3, multifunctional myosin adaptor in mammalian auditory hair cells

GIPC 3是Gα-相互作用蛋白C-末端（GIPC）家族的成员，已知GIPC 3是GIPC家族中的一员， 听证会GIPC 3中的11个突变遍布其三个结构域，导致遗传性 常染色体隐性遗传性听力损失然而，GIPC 3在听觉系统中功能的分子基础 这些人类突变导致听力损失的机制和系统尚不清楚。我们 最近已经确定了与原型受体结合的GIPC 3的结构，并确定了GIPC 3的结构。 GIPC 3激活及其随后与MYO 6结合的分子机制， 在听觉毛细胞中表达的肌球蛋白，对听觉至关重要。这些生物化学和 结构研究使我们能够预测GIPC 3中已知的与生育相关的突变对其生育能力的影响。 激活和MYO 6结合。我们已经产生了两个新的小鼠模型，一个是缺乏功能， GIPC 3和另一个GIPC 3中具有W301 X点突变的突变，该突变对应于GIPC 3的突变。 最严重的听觉表型。这项研究将探讨中心假设，即GIPC 3具有 听觉毛细胞的双重作用。我们假设，在静纤毛中，GIPC 3参与了成形， 通过与CDH 23/肌球蛋白-VIIa的相互作用， myosin-XVa。在细胞体中，GIPC 3对于表皮周的顶端内吞作用是必需的。 由于其与肌球蛋白-VI的相互作用，所有这些功能对正常的听力都至关重要。 然而，决定机械传导中静息张力的确切分子机制- 听毛细胞束的结构及静纤毛高度和直径的分级 仍然是个谜同样地，我们对分子机制，甚至是蛋白质的作用知之甚少。 表皮周无颈内吞在毛细胞中的作用。本研究的预期结果是 揭示（a）与GIPC 3缺陷相关的耳聋的确切机制和（B） GIPC 3在毛细胞功能中的生理作用，特别是在机械转导、毛发形成中的生理作用 维管束结构和胞吞作用。解读GIPC 3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GIPC 3依赖性耳聋和听力损失。

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.