The specialized role of Hsp70 in protein import

Hsp70 在蛋白质输入中的特殊作用

• 批准号: 7274995
• 负责人: Thomas Lee
• 金额: $ 4.96万
• 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 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7274995
• 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（由申请人提供）：70 kDa热休克蛋白（Hsp70），也称为分子伴侣，除了在蛋白质折叠中的一般作用外，还在专门的生物过程中发挥作用。例如，主要的线粒体Hsp70（mtHsp70）在蛋白质跨线粒体内膜的输入中起核心作用。由于绝大多数线粒体蛋白质是在胞质核糖体上合成的，因此有效的蛋白质易位对于线粒体生物发生是至关重要的，如内膜易位酶（TIM）和基于mtHsp70的“输入马达”的组分的基本性质所示。Tim 44是TIM复合物的外周膜成分，被认为是mtHsp70与输入通道的系链，并在结合底物蛋白（易位多肽）后将其从易位酶中释放出来。然而，很少有人了解mtHsp70：Tim44相互作用和背后的mtHsp70：Tim44复合物肽结合不稳定的机制。该提案的目标是更好地了解“输入马达”和TIM复合物的分子伴侣组分之间的相互作用及其在易位过程中的重要性。使用酿酒酵母作为模型系统，我的目的是剖析mtHsp70：Tim44相互作用和测试的重要性，这种相互作用的动态性质的蛋白质易位。我的实验结果将提供深入了解这一重要的生物学过程，以及作为一个例子，热休克蛋白70如何进化出特定的调节蛋白质：蛋白质相互作用，使他们能够在专门的生物过程中发挥作用，同时利用其基本的生化特性：与氨基酸的短疏水片段的相互作用。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大的治疗和糖尿病。此外，线粒体的生物发生依赖于在细胞质中翻译的数百种蛋白质的蛋白质易位，线粒体部分地涉及许多疾病（例如神经系统疾病、癌症和代谢疾病）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。