Myosin XVA and Other Genes Essential for Stereocilia Morphogenesis

肌球蛋白 XVA 和其他对于立体纤毛形态发生至关重要的基因

• 批准号: 8349623
• 负责人: Thomas Friedman
• 金额: $ 111.99万
• 依托单位: NATIONAL INSTITUTE ON DEAFNESS AND OTHER COMMUNICATION DISORDERS
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8349623
• 关键词: 17p11.2; Actins; Alleles; Alternative Splicing; Auditory system; Binding; Biological; Bundling; Chromosomes; Collaborations; Data; Endocrine; Exons; Extramural Activities; Family; Genes; Hair Cells; Head; Hearing; Hearing Impaired Persons; Human; Kinetics; Knockout Mice; Laboratories; Labyrinth; Light; Link; Molecular Motors; Morphogenesis; Motor; Mus; Mutate; Mutation; Myosin ATPase; N-terminal; National Heart, Lung, and Blood Institute; National Institute on Deafness and Other Communication Disorders; Neck; Phenotype; Play; Population; Property; Protein Isoforms; Proteins; Reporting; Research Design; Role; Scientist; Stereocilium; Supporting Cell; Tail; Tissues; base; cell type; congenital deafness; deafness; mouse model; mutant; myosin XVA; protein function; yeast two hybrid system

Mutant alleles of mammalian myosin XVA cause profound congenital deafness DFNB3. In humans worldwide, mutations of MYO15A apepars to be the third most common mutated gene associated with deafness. Myosins are actin based molecular motors that have a conserved head (motor) and neck (light chain binding motifs) and highly divergent tail domains. The MYO15A tail contains several motifs that are candidates for protein interaction motifs. To date, isoform 1 of myosin XVa is the largest of all reported vertebrate myosins. The N-terminus of myosin XVa is composed of 1,220 residues. We previously demonstrated that isoform 1 is necessary for hearing (Nal et al., 2007). As a collaboration with extramural scientists, a mouse model has been developed that has a defective amino terminus which recapitulates the human phenotype (unpublished data). The identification of proteins that functionally interact with MYO15 may provide a means of determining the role of MYO15A in the auditory system. In addition, interacting proteins are themselves likely to play crucial roles in hearing and would be strong candidates for proteins encoded by other deafness loci. We are therefore using a yeast two hybrid system and MS screens to identify proteins that interact with the myosin XVA. Genes that encode poteins that interact with myosin XVA from these two screens will be further examined for biological relevance. Whirlin is one such partner of the tail domain of myosin XVa and is necessary for stereocilia elongation and staircase formation (Belyantseva et al. 2005). We are also characterizing the biophysical properties of myosin XVa.

哺乳动物肌球蛋白 XVA 的突变等位基因导致严重的先天性耳聋 DFNB3。 在全世界人类中，MYO15A 突变似乎是与耳聋相关的第三大常见突变基因。 肌球蛋白是基于肌动蛋白的分子马达，具有保守的头部（马达）和颈部（轻链结合基序）以及高度分化的尾部结构域。 MYO15A 尾部包含多个作为蛋白质相互作用基序候选的基序。迄今为止，肌球蛋白 XVa 的异构体 1 是所有已报道的脊椎动物肌球蛋白中最大的。肌球蛋白 XVa 的 N 末端由 1,220 个残基组成。我们之前证明异构体 1 对于听力是必需的 (Nal et al., 2007)。通过与校外科学家的合作，开发了一种小鼠模型，该模型具有氨基末端缺陷，可以概括人类表型（未发表的数据）。 与 MYO15 功能性相互作用的蛋白质的鉴定可能提供一种确定 MYO15A 在听觉系统中的作用的方法。此外，相互作用的蛋白质本身可能在听力中发挥关键作用，并且可能是其他耳聋基因座编码的蛋白质的有力候选者。因此，我们使用酵母两种杂交系统和 MS 筛选来鉴定与肌球蛋白 XVA 相互作用的蛋白质。将进一步检查这两个筛选中编码与肌球蛋白 XVA 相互作用的蛋白的基因的生物学相关性。 Whirlin 是肌球蛋白 XVa 尾部结构域的伙伴之一，对于静纤毛伸长和阶梯形成是必需的 (Belyantseva et al. 2005)。 我们还描述了肌球蛋白 XVa 的生物物理特性。