Analysis of force developed by a AAA ATPase

AAA ATP酶产生的力分析

• 批准号: 8536863
• 负责人: SANFORD M SIMON
• 金额: $ 29.73万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-30 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8536863
• 关键词: ATP Hydrolysis; ATP phosphohydrolase; Address; Affect; Amino Acids; Apoptosis; Bacteria; Binding; Biogenesis; Biological Clocks; Biology; Cell Cycle; Cell division; Cell physiology; Clinical Treatment; Clinical Trials; Commit; Decision Trees; Devices; Digestion; Failure; Family; Gene Expression Regulation; Generations; Genetic Transcription; Goals; Half-Life; Hand; Health; Human; Individual; Length; Malignant Neoplasms; Measurement; Measures; Methods; Mitochondria; Modeling; Molecular Machines; Movement; Multiple Myeloma; Multivesicular Body; Mutate; Nervous System Trauma; Outcome; Pathology; Performance; Property; Proteasome Inhibitor; Proteins; Proteolysis; Recurrence; Regulation; Role; Side; Signal Transduction Pathway; Site; Statistical Distributions; Stress; Surface; System; Techniques; Testing; Therapeutic Intervention; Time; Transport Protein Gene; War; Work; antigen processing; desensitization; human disease; insight; member; multicatalytic endopeptidase complex; polypeptide; protein degradation; receptor; single molecule

DESCRIPTION (provided by applicant): The AAA ATPases family includes molecules whose roles include, but are far from limited to, biogenesis of mitochondria and multivesicular bodies, proteins in involved in gene regulation and protein transport. This project will focus on studying the activity of these machines at the single molecule level. The model protein will be ClpX - it is the part of the proteosome, a key effect of protein degradation that unfolds the proteins to prepare them for degradation. . Cellular proteins differ widely in their liability, from half-lives of minutes to days. Regulated degradation, by allowing rapid changes in the levels of cellular proteins, helps control signal transduction pathways, the cell- cycle, transcription, apoptosis, antigen processing, biological clock control, differentiation and surface receptor desensitization. The questions to be addressed are: How is work partitioned between alternative outcomes? What is the maximum work that can be performed by the system? What factors limit its efficiency in performing work? These questions have health implications: human pathological conditions are associated with failures of the degradation system and its regulation offers the potential for therapeutic intervention. Furthermore, an inhibitor of proteasome catalytic activity is in use for treatment of recurrent multiple myeloma, and proteasome inhibitors are in clinical trial for treatment of a broad spectrum of human malignancies. Thus, understanding the regulation of the half-life of proteins should provide critical insights into cell physiology and pathology. The mishandling of aberrant proteins incurs penalties throughout biology: the survival of bacteria subjected to stress depends on the effective performance of systems which deal with misfolded and structurally aberrant proteins- to either fold them properly or destroy them. The specific questions to be addressed are: How hard can the device pull to cause unfolding? How many pulls are needed to commit irreversibly? What is the limit of pulling power, and the statistical distribution of pulling power? Answers to these questions will begin to reveal not just what these machines do but the decision tree that describes how outcomes are controlled and when machine capacity may be exceeded. We want to know not just how the machine works, but how its decision tree yields alternative outcomes.

描述（由申请人提供）：AAA ATP酶家族包括其作用包括但不限于线粒体和多泡体的生物发生、参与基因调控和蛋白质运输的蛋白质的分子。该项目将重点研究这些机器在单分子水平上的活动。模型蛋白质将是 ClpX - 它是蛋白质体的一部分，蛋白质降解的关键作用是展开蛋白质，为降解做好准备。 。细胞蛋白质的作用差异很大，半衰期从几分钟到几天不等。通过允许细胞蛋白质水平的快速变化，调节降解有助于控制信号转导途径、细胞周期、转录、细胞凋亡、抗原加工、生物钟控制、分化和表面受体脱敏。要解决的问题是：如何在不同的结果之间分配工作？系统可以执行的最大工作量是多少？哪些因素限制了其执行工作的效率？这些问题具有健康影响：人类病理状况与降解系统的故障有关，其调节提供了治疗干预的潜力。此外，蛋白酶体催化活性的抑制剂用于治疗复发性多发性骨髓瘤，并且蛋白酶体抑制剂正在进行用于治疗多种人类恶性肿瘤的临床试验。因此，了解蛋白质半衰期的调节应该为细胞生理学和病理学提供重要的见解。对异常蛋白质的错误处理会在整个生物学中招致惩罚：受到压力的细菌的生存取决于处理错误折叠和结构异常蛋白质的系统的有效性能——要么正确折叠它们，要么破坏它们。要解决的具体问题是：设备能用多大的力拉才能展开？需要多少拉动才能不可逆转地提交？拉力的极限是多少，以及拉力的统计分布？这些问题的答案不仅会揭示这些机器的功能，还会揭示描述如何控制结果以及何时可能超出机器容量的决策树。我们不仅想知道机器是如何工作的，还想知道它的决策树如何产生替代结果。