Role of Valosin-Containing Protein (VCP/p97) in Cadmium-Disturbed Proteostasis

含 Valosin 的蛋白 (VCP/p97) 在镉干扰的蛋白质稳态中的作用

• 批准号: 8570167
• 负责人: Changcheng Charlie Song
• 金额: $ 23.26万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-15 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8570167
• 关键词: ATP Hydrolysis; ATP phosphohydrolase; ATPase Domain; Advanced Development; Affect; Affinity; Agreement; Attenuated; Binding; Binding Sites; Biochemical; Biological; Cadmium; Cause of Death; Cells; Chemicals; Chronic; Chronic Disease; Chronic Obstructive Airway Disease; Cystic Fibrosis Transmembrane Conductance Regulator; Cytoplasm; Development; Disease; Endoplasmic Reticulum; Environment; Environmental Pollutants; Environmental Pollution; Exposure to; Family; Functional disorder; Goals; Half-Life; Health; Heart; Heavy Metals; Histidine; Homeostasis; Human; Human body; In Vitro; Injury; Ions; Kidney; Laboratories; Lung; Mediating; Metalloproteins; Molecular; Molecular Chaperones; Molecular Target; N Domain; Pathogenesis; Pathway interactions; Patients; Poisoning; Prevalence; Prevention; Preventive; Property; Proteins; Public Health; Quality Control; Reporting; Research; Respiratory System; Role; Skeletal system; Structure; System; Testing; Therapeutic; Trace Elements; Ubiquitin; Ubiquitinated Protein Degradation; United States; Vascular System; Zinc; alpha 1-Antitrypsin; base; cigarette smoking; cofactor; cytotoxicity; effective therapy; functional loss; functional restoration; improved; insight; member; multicatalytic endopeptidase complex; novel; pneumocyte; pollutant; prevent; protein degradation; protein function; protein misfolding; protein structure; public health relevance; therapy development; valosin-containing protein

DESCRIPTION (provided by applicant): Cadmium (Cd2+) poisoning is a serious health threat due to increased level of environmental pollution and lack of effective therapy. An extremely long biological half-life of Cd2+ in the human body leads to a persistent and cumulative effect. Chronic exposure to Cd2+ causes disorders of the nervous, renal, skeletal, vascular, and respiratory systems. A common pathophysiological feature of these seemingly unrelated diseases is imbalanced protein homeostasis (proteostasis). Evidence reported from our laboratory, as well as others, suggests that Cd2+ prevents the degradation of ubiquitinated proteins in human cells, and the cytotoxicity of Cd2+ can be alleviated by increasing the degrading capacity of the ubiquitin proteasome pathway in cells. However, Cd2+ does not affect proteasome activity directly. Why ubiquitinated proteins cannot be degraded in Cd2+ treated cells remains as a critical open question. Valosin-containing protein (VCP/p97), a molecular chaperone, lies at the heart of proteostasis to unfold ubiquitinated proteins for proteasomal degradation. A structural Zinc (Zn2+) located in the center pore of VCP is essential for ubiquitinated protein degradation. Since Cd2+ can substitute for Zn2+ in some proteins to change protein structure and protein function, we hypothesize that the replacement of the structural Zn2+ by Cd2+ results in loss of VCP function, and this leads to a reduction in ubiquitinated protein degradation. We propose to examine the ATPase activity and hexamer structure, two essential features of VCP in mediating protein degradation, as well as the biological actions of Cd2+-containing VCP, in an effort to understand the loss of functional activity. Our long-term goal is to define the biochemical basis for the disturbance of proteostasis underlying the protein misfolding induced by heavy metal ions. We believe these studies will contribute to a better understanding of the pathogenesis of Cd2+-associated diseases and advance the development of preventive and/or therapeutic strategies for these disorders. 1

描述（由申请人提供）：镉（CD2+）中毒是由于环境污染水平提高和缺乏有效治疗的严重健康威胁。人体中CD2+的生​​物半衰期非常长，会导致持续和累积的效果。长期暴露于CD2+会导致神经，肾脏，骨骼，血管和呼吸系统的疾病。这些看似无关的疾病的常见病理生理特征是蛋白质稳态不平衡（蛋白质稳态）。我们的实验室报告的证据以及其他证据表明，CD2+可防止人类细胞中泛素化蛋白的降解，并且可以通过增加细胞中泛素蛋白酶体途径的降解能力来减轻CD2+的细胞毒性。但是，CD2+不会直接影响蛋白酶体活动。为什么在CD2+处理的细胞中不能降解泛素化蛋白仍然是一个关键的开放问题。含瓣膜蛋白的蛋白质（VCP/p97）是一种分子伴侣，位于蛋白质的核心，以展现泛素化的蛋白质以降解蛋白酶体降解。 VCP中心孔中的结构锌（Zn2+）对于泛素化蛋白质降解至关重要。由于CD2+可以在某些蛋白质中代替Zn2+改变蛋白质结构和蛋白质功能，因此我们假设用CD2+替换结构Zn2+会导致VCP功能的丧失，这导致泛素化蛋白质降解的减少。我们建议检查ATPase活性和六聚体结构，这是VCP介导蛋白质降解中的两个基本特征，以及CD2+含有CD2+的VCP的生物学作用，以了解功能活性的丧失。我们的长期目标是定义疾病的生化基础 重金属离子引起的蛋白质错误折叠的基础。我们认为，这些研究将有助于更好地理解CD2+相关疾病的发病机理，并推动针对这些疾病的预防和/或治疗策略的发展。 1