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PROTEIN CARBOXYL METHYLATION AND NEURONAL FUNCTION

蛋白质羧基甲基化与神经元功能

基本信息

批准号：
3074926
负责人：
DANA WILLIAM ASWAD
金额：
$ 5.63万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
1986
资助国家：
美国
起止时间：
1986-03-01 至 1991-02-28
项目状态：
已结题

项目摘要

The overall goal of this project is to understand the role of protein carboxyl methylation in neuronal function. There are two current hypotheses of methylation function in eucaryotes: (1) that it mediates some aspect of stimulus-response coupling via the reversible modification of protein function, and (2) that it facilitates the repair or degradation of defective proteins which contain abnormal forms of aspartic acid. In testing the regulation hypothesis, we propose to measure the ability of certain neurotransmitters and depolarizing agents to stimulate transient protein methylation (as indicated by the evolution of radiolabeled methanol), to search in purified subfractions of brain for specific protein which serve as preferential substrates in an in vitro transient methylation assay, and, to determine if the in vitro transient methylation reaction is regulated by the second messengers cAMP, cGMP, Ca++ or phosphatidyl inositol. Our strategy in these experiments is derived from recent indications that carboxyl methylation may serve as an initial activation step in a more complex protein modification reaction than hitherto assumed. An alternative role for carboxyl methylation in the repair or degradatiom of damaged proteins is suggested by the recently discovered selectivity of the methyltransferase enzyme for proteins containing abnormal forms of aspartate, particularly L-isoaspartyl and D-aspartyl residues. We propose to determine if the methyl accepting substrates we have located in synaptic membranes and myelin are enriched in these atypical forms of aspartate, and, to determine if the levels of these abnormal proteins and/or the methyltransferase enzyme changes significantly with age in the human or in association with Alzheimer's disease. Establishing a firm role for carboxyl methylation should provide important new insight on fundamental mechanisms of cellular regulation and/or aging processes in the mammalian nervous system.

这个项目的总体目标是了解蛋白质的作用羧基甲基化在神经元功能中的作用目前有两个真核生物中甲基化功能的假说：（1）它介导一些通过可逆修饰的刺激-反应偶联方面蛋白质功能，和（2）它促进修复或降解含有异常形式天冬氨酸的缺陷蛋白质。在检验监管假设，我们建议衡量的能力，某些神经递质和去极化剂刺激短暂的蛋白质甲基化（如放射性标记的演变所示）甲醇），以在纯化的脑亚组分中寻找特定的蛋白质其在体外瞬时甲基化中作为优先底物测定，并确定体外瞬时甲基化反应是否是受第二信使cAMP、cGMP、Ca++或磷脂酰调节肌醇。我们在这些实验中的策略来自于最近的表明羧基甲基化可以作为初始活化在比迄今为止更复杂蛋白质修饰反应中的步骤假设。羧基甲基化在修复或最近发现的蛋白质降解现象表明，甲基转移酶对含有天冬氨酸的异常形式，特别是L-异戊酰基和D-戊酰基残基我们建议确定甲基接受底物，位于突触膜中，髓鞘在这些膜中富集非典型形式的天冬氨酸，并确定这些水平异常蛋白质和/或甲基转移酶显著改变与人类年龄或阿尔茨海默病有关。确定羧基甲基化的作用将提供重要的对细胞调节和/或衰老的基本机制的新见解哺乳动物神经系统中的神经过程。