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(申请人提供)：镉(镉)中毒是一个严重的健康威胁，因为环境污染水平增加和缺乏有效的治疗方法。镉在人体内具有极长的生物半衰期，会产生持久的累积效应。慢性接触镉会导致神经、肾脏、骨骼、血管和呼吸系统的紊乱。这些看似无关的疾病的一个共同的病理生理特征是不平衡的蛋白质稳态(蛋白质稳态)。本实验室和其他实验室报道的证据表明，Cd~(2+)可以阻止人类细胞中泛素化蛋白的降解，而Cd~(2+)的细胞毒性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。然而，Cd~(2+)并不直接影响蛋白酶体的活性。为什么泛素化的蛋白质不能在CD2+处理的细胞中被降解仍然是一个关键的悬而未决的问题。含有Valosin的蛋白(VCP/p97)是一种分子伴侣，位于蛋白调控的核心，为蛋白酶体的降解提供泛素化的蛋白。位于VCP中心孔中的结构锌是泛素化蛋白质降解所必需的。由于Cd~(2+)可以替代某些蛋白质中的Zn~(2+)来改变蛋白质的结构和功能，我们推测Cd~(2+)取代结构上的锌~(2+)会导致VCP功能的丧失，从而导致泛素化蛋白质降解的减少。我们建议研究VCP在调节蛋白质降解过程中的两个基本特征--ATPase活性和六聚体结构，以及含Cd~(2+)的VCP的生物学作用，以努力了解VCP功能活性的丧失。我们的长期目标是确定蛋白质平衡紊乱的生化基础。 在重金属离子诱导蛋白质错误折叠的基础上。我们相信这些研究将有助于更好地了解CD2+相关疾病的发病机制，并推动针对这些疾病的预防和/或治疗策略的发展。1