Structure-Function of the Nuclear Envelope Bridge and its Role in Laminopathies

核膜桥的结构-功能及其在核纤层蛋白病中的作用

• 批准号: 8816200
• 负责人: Thomas Schwartz
• 金额: $ 31.23万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-15 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8816200
• 关键词: ATP phosphohydrolase; Affect; Biochemical; Biological Process; Cancer Etiology; Cardiomyopathies; Cell Nucleus; Cells; Cerebellar Ataxia; Chromatin; Chromosome Pairing; Complex; Cytoplasm; Cytoskeleton; Data; Defect; Disease; Drug Targeting; Emery-Dreifuss Muscular Dystrophy; Employee Strikes; Etiology; Face; Funding; Future; Genes; Grant; Health; Homologous Gene; Human; Immunoglobulin Fragments; Lamin Type A; Lamin Type B; Lamins; Lead; Malignant Neoplasms; Mammalian Cell; Mechanics; Meiosis; Membrane Proteins; Molecular; Molecular Target; Muscle; Muscular Dystrophies; Mutation; Nuclear; Nuclear Envelope; Nuclear Inner Membrane; Nuclear Lamina; Nuclear Outer Membrane; Nuclear Pore Complex; Patients; Peptides; Pharmaceutical Preparations; Positioning Attribute; Premature aging syndrome; Procedures; Process; Progeria; Proteins; Regulation; Research; Role; Scheme; Side; Signal Transduction; Specificity; Structure; The Sun; Therapeutic; Time; Tissues; TorsinA; Translating; Translations; Transport Process; United States; Wasting Syndrome; Work; antibody engineering; base; comparative; design; disease-causing mutation; emerin; env Gene Products; human disease; insight; lissencephaly; migration; milligram; mimetics; novel; programs; protein aggregate; protein complex; reconstitution; research study; self assembly; tool; two-dimensional

DESCRIPTION (provided by applicant): In mammalian cells, A- and B-type lamins form a two-dimensional protein meshwork, the lamina, at the nucleoplasmic face of the nuclear envelope. Mutations scattered along the LMNA gene, which encodes A-type lamins, as well as mutations within other nuclear envelope proteins are associated with a broad range of human diseases collectively called laminopathies. The molecular etiology of these diseases remains unknown. Emery-Dreifuss muscular dystrophy (EDMD), the most prominent laminopathy, is an incurable, devastating muscular wasting disease, caused by mutations in either, the inner nuclear membrane (INM) protein emerin, laminA, or the outer nuclear membrane (ONM) KASH-proteins nesprins 1 and 2. The four proteins are connected via LINC complexes, evolutionary-conserved protein complexes between INM SUN-proteins and ONM KASH-proteins that bridge the faces of the nuclear envelope and physically connect the nuclear lamina to the cytoskeleton of mammalian cells. Taken together, the data suggests that EDMD is the result of aberrant nuclear positioning or, alternatively, aberrant mechanical signaling through the LINC complex. Furthermore, it has been shown that the over-accumulation of Sun1 at the INM is the pathological effector of EDMD. With funding through an exploratory R21 grant we have determined the core structure of the SUN-KASH complex in 2012, providing the first molecular insight into LINC complexes. Here, we build on this data and suggest a research program that should aid in the discovery of drug targets that hopefully will translate into a medication strateg for EDMD patients. This proposal outlines experiments that will lead A) to a comprehensive structural and biochemical understanding of the human SUN-KASH interactome, B) a structural basis for LINC complex anchorage to the lamin layer, and C) insight into the regulation of LINC complex assembly and disassembly. We expect that the pursuit of these three aims will yield a much better molecular description of the protein network that forms the basis of EDMD, and consequently will unveil possible drug targets that disrupt these processes. We further anticipate that this research will advance our understanding of the nuclear envelope in general, which will have a tangible impact on the vast array of pathological nuclear envelope disorders.

描述（由申请人提供）：在哺乳动物细胞中，A-和B型层粘蛋白形成二维蛋白网层，层层，在核包膜的核质面上。沿着LMNA基因散布的突变（编码A型层粘连蛋白）以及其他核包膜蛋白内的突变与广泛的人类疾病统称为椎板病。这些疾病的分子病因仍然未知。最突出的椎板病是一种无法治愈的，毁灭性的肌肉浪费疾病（由内部核膜（INM）蛋白Emerin，薄片，层或外部核膜（ONM）Kash-kash蛋白Nesprins 1和四蛋白质相结合的，是由两种蛋白质的蛋白质（INM）蛋白质，肌肉蛋白（INM）蛋白质（INM）蛋白质均与四个蛋白质相关联。 INM Sun-蛋白质和ONM Kash蛋白之间的蛋白质复合物，它们弥合了核包膜的面，并将核薄片物理地连接到哺乳动物细胞的细胞骨架。综上所述，数据表明EDMD是核位置异常的结果，或者是通过LINC络合物的异常机械信号传导。此外，已经表明，在INM处太阳1的过度蓄能是EDMD的病理效应子。通过探索性R21赠款的资金，我们在2012年确定了Sun-Kash复合物的核心结构，从而提供了对Linc Complexses的首次分子见解。在这里，我们以这些数据为基础，并提出了一项研究计划，该计划应有助于发现药物靶标，希望能够转化为EDMD患者的药物策略。该提案概述了将导致a）对人类sun-kash相互作用的全面结构和生化理解的实验，b）LINC复杂锚定在层层层层的结构基础，以及c）深入了解LINC COMPLECT组装和拆卸的调节。我们预计，对这三个目标的追求将产生构成EDMD基础的蛋白质网络的更好的分子描述，因此将揭示破坏这些过程的可能的药物靶标。我们进一步预计，这项研究将提高我们对核包络的理解，这将对众多的病理性核包络疾病产生切实的影响。