The specialized role of Hsp70 in protein import

Hsp70 在蛋白质输入中的特殊作用

• 批准号: 7418336
• 负责人: Thomas Lee
• 金额: $ 4.95万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-05-01 至 2009-04-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7418336
• 关键词: Affect; Aging-Related Process; Amino Acids; Binding; Biochemical; Biogenesis; Biological; Biological Assay; Biological Models; Biological Process; Cells; Communication; Complement; Complex; Cytosol; Data; Diabetes Mellitus; Disease; Dissociation; Genes; Genomics; Goals; Growth; Heart Hypertrophy; Heat shock proteins; Hydrogen; In Vitro; Inner mitochondrial membrane; Kinetics; Malignant Neoplasms; Mass Spectrum Analysis; Membrane; Metabolic Diseases; Mitochondria; Mitochondrial Proteins; Modeling; Molecular Chaperones; Motor; Nature; Peptides; Peripheral; Play; Process; Property; Protein Import; Protein translocation; Proteins; Public Health; Rate; Regulation; Resolution; Ribosomes; Role; Saccharomyces cerevisiae; Stretching; Suppressor Mutations; Testing; Thinking; Translating; Yeasts; base; driving force; improved; in vivo; insight; mutant; nervous system disorder; polypeptide; protein folding; protein protein interaction; research study; restoration; translocase

DESCRIPTION (provided by applicant): The 70 kDa Heat shock proteins (Hsp70s), also known as molecular chaperones, have evolved to function in specialized biological processes, in addition to the general role in protein folding. For example, the major mitochondrial Hsp70 (mtHsp70) plays a central role in protein import across the mitochondrial inner membrane. Since the vast majority of mitochondrial proteins are synthesized on cytosolic ribosomes, efficient protein translocation is critical for mitochondrial biogenesis, as indicated by the essential nature of components of the translocase of the inner membrane (TIM) and the mtHsp70 based "import motor". Tim44, a peripheral membrane component of the TIM complex, is believed to serve as a tether for mtHsp70 to the import channel and release it from the translocase upon binding a substrate protein, the translocating polypeptide. However, little is understood about the mtHsp70:Tim44 interaction and the mechanism behind the destabilization of the mtHsp70:Tim44 complex upon peptide binding. The goal of this proposal is to better understand the interaction between chaperone components of the "import motor" and the TIM complex and their importance in the translocation process. Using Saccharomyces cerevisiae as a model system, I aim to dissect the mtHsp70:Tim44 interaction and test the importance for the dynamic nature of this interaction on protein translocation. The results of my experiments will provide insight into this important biological process, as well as serve as an example of how Hsp70s have evolved specific regulated protein:protein interaction that allow them to function in specialized biological processes while utilizing their fundamental biochemical property: interaction with short hydrophobic segments of amino acids. Recent genomic data suggested that the regulation of expression of import motor components may be involved in heart hypertrophy treatments and diabetes. Moreover, mitochondria, whose biogenesis depends upon protein translocation of hundreds of proteins translated in the cytosol, are involved, in part, in numerous diseases (e.g. neurological disorders, cancer, and metabolic diseases), as well as the aging processes, indicating that the basic cell biological problems converge on the issues of public health.

描述(申请人提供)：70 kDa热休克蛋白(Hsp70)，也被称为分子伴侣，除了在蛋白质折叠中的一般作用外，还进化成在特殊的生物学过程中发挥作用。例如，主要的线粒体Hsp70(MtHsp70)在跨线粒体内膜的蛋白质输入中起着核心作用。由于绝大多数线粒体蛋白是在胞质核糖体上合成的，有效的蛋白质易位对线粒体的生物发生至关重要，内膜转位酶(Tim)和基于mtHsp70的“输入马达”的基本性质表明了这一点。Tim44是TIM复合体的外周膜成分，被认为是mtHsp70与输入通道的纽带，并在结合底物蛋白(转位多肽)后从转位酶中释放出来。然而，关于mtHsp70：Tim44的相互作用以及mtHsp70：Tim44复合体在肽结合时失稳的机制还知之甚少。这项建议的目的是为了更好地了解“进口马达”的伴侣组件和TIM复合体之间的相互作用及其在易位过程中的重要性。以酿酒酵母为模型系统，分析mtHsp70：Tim44相互作用，并测试这种相互作用的动力学性质在蛋白质易位中的重要性。我的实验结果将使我们深入了解这一重要的生物学过程，并成为Hsp70如何进化出特定调控蛋白质的一个例子：蛋白质之间的相互作用使它们能够在特殊的生物学过程中发挥作用，同时利用它们的基本生化特性：与氨基酸的短疏水片段相互作用。最近的基因组数据表明，输入运动成分的表达调控可能参与心脏肥厚治疗和糖尿病的治疗。此外，线粒体的生物发生依赖于胞浆中数百种蛋白质的转位，部分参与了许多疾病(如神经疾病、癌症和代谢性疾病)以及衰老过程，这表明基本的细胞生物学问题集中在公共卫生问题上。