Myosins VIIA, VIIB & XV in Fly Hearing and Morphogenesis

肌球蛋白VIIA、VIIB

基本信息

批准号：
7640647
负责人：
DANIEL PETER KIEHART
金额：
$ 32.39万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-07-15 至 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7640647
关键词：
Actins Address Adhesions Adult Affinity Animals Auditory Binding Biological Models Biological Process Biology Cell physiology Cells Complex Cytoskeleton Development Drosophila genus Drosophila melanogaster Electron Microscopy Elements Embryo Gene Proteins Genetic Hair Hearing Heart Human In Vitro Individual Interdisciplinary Study Loa Mediating Membrane Methods Microfilaments Microtubules Molecular Molecular Genetics Molecular Machines Morphogenesis Motor Mus Mutate Mutation Myosin ATPase Organ Orthologous Gene Phenotype Physiology Play Process Proteins Recombinant Proteins Research Personnel Resolution Role SH3 Domains Sensory Signal Transduction Specific qualifier value Structure System Tail Work Yeasts base design fly hybrid protein in vivo insight interdisciplinary approach member novel programs protein complex protein function protein structure protein structure function relating to nervous system research study sound success tool transcription factor yeast two hybrid system

项目摘要

DESCRIPTION (provided by applicant): We propose a multidisciplinary research program that investigates the function of protein complexes at the heart of auditory reception in the model system, Drosophila melanogaster. The biology of hearing is astonishingly conserved between humans and fly: both the transcription factors that specify the development of organs of auditory reception and the molecular machines that transduce sound into neural signals are highly conserved. In both systems, cellular differentiation for the perception of sound requires elaborate subcellular arrangements of cytoskeletal elements, including actin filaments and microtubules. Mutations in the human and mouse orthologs of ck/myoVIIA and 10A/myoXV demonstrate the key roles these proteins play in auditory reception and vestibular function, but the molecular mechanism(s) by which these motor proteins contribute to these processes remain controversial. We propose an interdisciplinary approach to structure/function analysis of ck/myoVIIA, 28B/myoVIIB and 10A/myoXV (together, the myosin VII subfamily) in Drosophila where we use uniquely powerful molecular genetic tools to relate protein structure-function studies in vitro to structure/function analyses in vivo. We have already shown that ck/myoVIIA mutates to lethality, is required to drive changes in the structure of the actin cytoskeleton during morphogenesis and is required for auditory reception in adult flies. We have demonstrated that 10A/myoXV is essential for fly viability. We propose three specific aims 1) that address the cellular mechanisms of motor protein function; 2) that identify the binding partners with which these motor proteins interact; and 3) elucidate the structure of their cargo binding tails. Our specific aims will inform one another, but do not depend on one another's success. Together, our studies offer unique opportunities to probe the supramolecular protein complexes that require motor protein function and that drive cellular function in auditory reception, vestibular function and morphogenesis.

描述（由申请人提供）：我们提出了一个多学科研究计划，该计划研究了模型系统中听觉接收核心果蝇果蝇（Drosophila Melanogaster）蛋白质复合物的功能。听力的生物学在人类和苍蝇之间是惊人的：指定听觉接收器官的发展的转录因子，以及将声音转换为神经信号的分子机器都高度保守。在这两个系统中，对声音感知感知的细胞分化都需要细胞骨架元件的精心构造亚细胞排列，包括肌动蛋白丝和微管。 CK/Myoviia和10a/MyoxV的人类和小鼠直系同源物中的突变证明了这些蛋白质在听觉接收和前庭功能中起着关键作用，但是这些运动蛋白对这些过程有助于这些过程的分子机制仍然有争议。我们提出了一种跨学科的方法，用于在果蝇中对CK/Myoviia，28b/Myoviib和10a/MyoxV（一起，肌球蛋白VII亚科）进行结构/功能分析，在其中我们使用独特的强大分子遗传工具来将蛋白质结构 - 蛋白质结构 - 蛋白质结构 - 在VIV In VIV In Vive Interfrount intucto intterroto interty in viv in viv contucto in viv in viv contrount。我们已经表明，CK/Myoviia突变为致死性，需要在形态发生过程中驱动肌动蛋白细胞骨架结构的变化，并且是成年蝇中听觉接收所必需的。我们已经证明了10A/MyoxV对于飞行生存能力至关重要。我们提出了三个特定目的1）解决运动蛋白功能的细胞机制； 2）识别这些运动蛋白相互作用的结合伙伴； 3）阐明其货物结合尾巴的结构。我们的具体目标将互相告知，但不依赖彼此的成功。我们的研究共同提供了独特的机会来探测需要运动蛋白功能的超分子蛋白质复合物，并在听觉接收，前庭功能和形态发生中驱动细胞功能。