Defining Effects of Myosin VII Structure and Kinetics on Hereditary Deafness

肌球蛋白 VII 结构和动力学对遗传性耳聋的影响

• 批准号: 7483614
• 负责人: Harvey F. Chin
• 金额: $ 4.1万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7483614
• 关键词: ATP phosphohydrolase; Actins; Binding; Biochemical; Biochemistry; Biological; Biological Process; Brush Border; Cell membrane; Cell physiology; Cells; Cellular Structures; Class; Coiled-Coil Domain; Cytoskeleton; Data; Defect; Development; Dimerization; Disease; Ear; Employee Strikes; Enzymes; Equilibrium; Eukaryota; Eukaryotic Cell; Eye; Family; Functional disorder; Goals; Hair Cells; Head; Human; Inherited; Intestines; Kinetics; Labyrinth; Length; Link; Maintenance; Mammals; Measures; Mechanics; Membrane; Methods; Microfilaments; Modeling; Molecular; Molecular Models; Molecular Motors; Motor; Motor Activity; Movement; Muscle Contraction; Mutation; Myosin ATPase; Organism; Patients; Phenotype; Property; Proteins; Public Health; Range; Rate; Research; Role; Solutions; Stereocilium; Structure; Syndrome; Thinking; Tissues; Transmembrane Transport; Transport Vesicles; Usher Syndrome; Variant; Vertebrates; Work; analytical ultracentrifugation; base; cell motility; cellular microvillus; deafness; dimer; disease phenotype; gastrointestinal microvillus; insight; interest; monomer; mouse model; mutant; receptor; sedimentation equilibrium; single molecule

DESCRIPTION (provided by applicant): Myosin VII belongs to the myosin family of actin-activated ATPase motor proteins responsible for generating force on the actin cytoskeleton in eukaryotes. In mammals, myosin VII is generally expressed in polarized cellular structures that form ordered arrays of actin-rich protrusions. Based on phenotypes of mutant organisms and biochemical studies demonstrating that myosin VII dwells in a state strongly-bound to actin, this myosin is thought to act primarily as an anchor by maintenance of tension between the cytoskeleton and membrane components in these structures. Mutations in myosin Vila results in one of the most common forms of inherited deafness in humans, but the molecular basis of disease presentation is currently unknown. Despite its biomedical importance, the structural and kinetic details that dictate how this motor performs its cellular functions are currently lacking. The long term goal of this proposal is to gain an understanding of the enzymatic and structural adaptations in myosin VII and how these contribute to precise biological function. Specifically, the first aim of this proposal is to identify how mutations that generate deafness phenotypes in humans disrupt the enzymatic and motor properties of myosin Vila. The second aim is to determine the oligomeric state of native myosin VII, which is necessary to develop a complete model of myosin VII function and motility in cells. As a whole, the work described in this proposal is directed towards the attainment of a more complete model for myosin VII function and will provide insight to the molecular basis of deafness that results from myosin VII dysfunction. Relevance to public health: Mutations in myosin Vila are directly associated with the development of Usher syndrome type Ib (and various other forms of inherited deafness), comprising one of the largest causes of inherited deafness-blindness syndromes in humans. A fundamental reason for the current lack of treatment options for patients with these diseases is a limited understanding of the molecular basis for myosin VII function in the ear and eye. The proposed research focuses on understanding how myosin VII functions as a molecular motor to better understand how loss of myosin VII motor activity leads to deafness.

描述（由申请方提供）：肌球蛋白VII属于肌动蛋白激活ATP酶马达蛋白的肌球蛋白家族，负责在真核生物中对肌动蛋白细胞骨架产生作用力。在哺乳动物中，肌球蛋白VII通常在极化的细胞结构中表达，这些结构形成富含肌动蛋白的突起的有序阵列。基于突变生物体的表型和生物化学研究，证明肌球蛋白VII处于与肌动蛋白强结合的状态，认为该肌球蛋白主要通过维持这些结构中细胞骨架和膜组分之间的张力而起锚作用。肌球蛋白Vila的突变导致人类遗传性耳聋的最常见形式之一，但疾病表现的分子基础目前尚不清楚。尽管其生物医学的重要性，结构和动力学的细节，决定了这个电机如何执行其细胞功能目前缺乏。该提案的长期目标是了解肌球蛋白VII的酶和结构适应以及这些适应如何有助于精确的生物学功能。具体来说，本提案的第一个目的是确定在人类中产生耳聋表型的突变如何破坏肌球蛋白Vila的酶和运动特性。第二个目的是确定天然肌球蛋白VII的寡聚状态，这是必要的，以开发一个完整的模型肌球蛋白VII的功能和运动细胞。作为一个整体，在这个建议中描述的工作是针对实现一个更完整的模型肌球蛋白VII功能，并将提供洞察耳聋的分子基础，导致肌球蛋白VII功能障碍。与公共卫生的相关性：肌球蛋白Vila的突变与Usher综合征Ib型（以及各种其他形式的遗传性耳聋）的发展直接相关，该综合征是人类遗传性失明综合征的最大原因之一。目前对这些疾病患者缺乏治疗选择的一个根本原因是对耳和眼肌球蛋白VII功能的分子基础的了解有限。拟议的研究重点是了解肌球蛋白VII如何作为分子马达发挥作用，以更好地了解肌球蛋白VII运动活性的丧失如何导致耳聋。