ENYZMES AFFECTING THE ACCUMULATION OF ALTERED PROTEINS

影响改变蛋白质积累的酶

• 批准号: 6631470
• 负责人: STEVEN G CLARKE
• 金额: $ 22.59万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-06-15 至 2005-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6631470
• 关键词: Arabidopsis; Caenorhabditis elegans; Escherichia coli; Saccharomyces cerevisiae; aging; aspartate; enzyme mechanism; gene mutation; grain; methyltransferase; protein metabolism

DESCRIPTION: (Adapted from the Application). The manifestations of aging result in part from cells becoming less efficient at self-repair with time. These reactions represent one part of the battle of organisms to maintain the structural integrity of essential macromolecules in the face of the molecules intrinsic instabilities. Defects in these mechanisms may underlie pathologies where the aging process can be accelerated. The objective of this work is to understand how aging organisms prevent the accumulation of covalently altered proteins that can compromise cellular functions. These investigators will characterize the role of the protein L-isoaspartate (D-aspartate) O-methyltransferase that recognizes spontaneously-damaged proteins and catalyzes the initial step of a protein repair reaction. The discovery of this pathway reveals that macromolecular repair may not be just for DNA, but for proteins as well. These investigators propose to ask how the potential accumulation of damaged proteins in aging is reduced by methylation and other pathways in viva. They will utilize model organisms including bacteria, yeast, worms, and plants. Specifically, we will characterize protein damage in the bacterium Escherichia coli. They will study mutant phenotypes of both the methyltransferase pcm gene and the sure gene shown to be present in an operon with pcm. They will also study the role of associated enzymes that are involved in the metabolism of isoaspartyl-containing proteins and peptides, including isoaspartyl dipeptidases. They will analyze mutants of the protein repair methyltransferase in the nematode worm Casnorhabditis elegant. They will ask how the yeast Saccharomyces cerevisiae can avoid the accumulation of proteins containing altered aspartyl residues in spite of the fact that it naturally lacks the methyltransferase. Finally, they will examine the role of the methylation reaction in controlling protein damage in higher plants, including corn and Arabidopsis. These studies will hopefully not only provide a new window to view protein life but may also suggest that the biological aging process may be closely linked to how well cells can keep polypeptides free of spontaneous covalent damage.

描述：（从应用程序改编）。 衰老的表现 随着时间的流逝，细胞在自我修复方面的效率变得降低了。 这些反应代表了生物战役的一部分，以维持 面对分子的基本大分子的结构完整性 内在的不稳定性。 这些机制的缺陷可能是病理的基础 衰老过程可以加速的地方。 这项工作的目的是 了解衰老的生物如何阻止共价改变 可能损害细胞功能的蛋白质。 这些调查人员会 表征蛋白质L-异冬酸酯（D-天冬氨酸）的作用 O-甲基转移酶，识别自发损害的蛋白质和 催化蛋白质修复反应的初始步骤。 发现 该途径表明，大分子修复可能不仅是DNA，而是 对于蛋白质也是如此。 这些调查人员建议询问潜力如何 通过甲基化和其他 viva的途径。 他们将利用包括细菌在内的模型生物， 酵母，蠕虫和植物。 具体而言，我们将表征蛋白质损伤 在细菌大肠杆菌中。 他们将研究 甲基转移酶PCM基因和证明存在于 带有PCM的操纵子。 他们还将研究相关酶的作用 参与了含异源质基蛋白的代谢和 肽，包括等冬酰胺基二肽酶。 他们将分析突变体 蛋白质修复甲基转移酶在线虫蠕虫casnorhabditis中 优雅的。 他们会问酿酒酵母如何避免 尽管有改变的蛋白质的积累 它自然缺乏甲基转移酶的事实。 最后，他们会的 检查甲基化反应在控制蛋白质损伤中的作用 较高的植物，包括玉米和拟南芥。 这些研究希望 不仅提供了一个新窗口来查看蛋白质寿命，而且还可能表明 生物老化过程可能与细胞如何保持如何保持紧密联系 多肽没有自发共价损伤。

项目成果

Yeast, plants, worms, and flies use a methyltransferase to metabolize age-damaged (R,S)-AdoMet, but what do mammals do?

酵母、植物、蠕虫和苍蝇使用甲基转移酶来代谢因年龄受损的 (R,S)-AdoMet，但哺乳动物会做什么呢？

• DOI: 10.1089/rej.2009.0956
• 发表时间: 2010
• 期刊: Rejuvenation research
• 影响因子: 2.6
• 作者: Vinci,ChrisR;Clarke,StevenG
• 通讯作者: Clarke,StevenG

Intracellular protein modification associated with altered T cell functions in autoimmunity.

细胞内蛋白质修饰与自身免疫中 T 细胞功能的改变相关。

• DOI: 10.4049/jimmunol.177.7.4541
• 发表时间: 2006
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Yang,Mei-Ling;Doyle,HesterA;Gee,RenelleJ;Lowenson,JonathanD;Clarke,Steven;Lawson,BrianR;Aswad,DanaW;Mamula,MarkJ
• 通讯作者: Mamula,MarkJ

Protein repair methyltransferase from the hyperthermophilic archaeon Pyrococcus furiosus. Unusual methyl-accepting affinity for D-aspartyl and N-succinyl-containing peptides.

来自超嗜热古菌激烈火球菌的蛋白质修复甲基转移酶。

• DOI: 10.1074/jbc.m108261200
• 发表时间: 2002
• 期刊: The Journal of biological chemistry
• 作者: Thapar,Nitika;Griffith,ScottC;Yeates,ToddO;Clarke,Steven
• 通讯作者: Clarke,Steven

Recognition of age-damaged (R,S)-adenosyl-L-methionine by two methyltransferases in the yeast Saccharomyces cerevisiae.

酿酒酵母中两种甲基转移酶对年龄损伤的 (R,S)-腺苷-L-甲硫氨酸的识别。

• DOI: 10.1074/jbc.m610029200
• 发表时间: 2007
• 期刊: The Journal of biological chemistry
• 作者: Vinci,ChrisR;Clarke,StevenG
• 通讯作者: Clarke,StevenG

Crystal structure of human L-isoaspartyl methyltransferase.

人 L-异天冬氨酰甲基转移酶的晶体结构。

• DOI: 10.1074/jbc.m200229200
• 发表时间: 2002
• 期刊: The Journal of biological chemistry
• 作者: Ryttersgaard,Carsten;Griffith,ScottC;Sawaya,MichaelR;MacLaren,DuncanC;Clarke,Steven;Yeates,ToddO
• 通讯作者: Yeates,ToddO