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GIPC3, multifunctional myosin adaptor in mammalian auditory hair cells

GIPC3，哺乳动物听毛细胞中的多功能肌球蛋白适配器

基本信息

批准号：
10624964
负责人：
Gregory I Frolenkov
金额：
$ 55.7万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-10 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10624964
关键词：
Actins Adopted Affect Age Age Months Ankle Apical Architecture Auditory Auditory system Belief Binding Biochemical Biochemistry C-terminal CDH23 gene Cadherin Domain Cell physiology Cells Cellular Structures Complex Consensus Coupling Custom DLG4 gene Data Development Diameter Dimerization Endocytosis Epidermal Growth Factor Receptor Pathway Substrate 8 Family Family member Hair Hair Cells Hearing Height Human Inherited Inner Hair Cells Knowledge Label Labyrinth Link MYO7A gene Mechanics Mediating Molecular Motor Mouse Strains Mus Mutation Myosin ATPase N-terminal Outcome Study Patients Phenotype Physiological Point Mutation Positioning Attribute Prevention Protein Family Proteins Receptor Activation Reporting Rest Role Shapes Site Structure Surface Synaptic Transmission Therapeutic Time Ubiquitin Vesicle WHRN gene autosome cell type deaf deafness dimer hearing impairment in vivo insight live cell imaging mechanotransduction member mouse model mutant myosin VI myosin XVA nanobodies normal hearing novel prevent receptor receptor binding response structural biology therapy development trafficking two-photon uptake

项目摘要

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.

GIPC3是g α-相互作用蛋白（Gα-Interacting Protein, C-terminus， GIPC）家族的一员，已知是基因的重要组成部分