Untersuchung des Einflusses post-translationaler Lysin Acetylierung als globaler Regulator des Zytoskeletts

研究翻译后赖氨酸乙酰化作为细胞骨架全局调节剂的影响

• 批准号: 200568056
• 负责人: Professor Dr. Michael Lammers
• 金额: --
• 依托单位: Institut für Biochemie
• 依托单位国家: 德国
• 项目类别: Independent Junior Research Groups
• 财政年份: 2011
• 资助国家: 德国
• 起止时间: 2010-12-31 至 2014-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/200568056?language=en
• 关键词: Untersuchung; des; Einflusses; post; translationaler

The availability of lysine-deacetylase inhibitors, acetyl-lysine specific antibodies and the enormous progress in quantitative proteomics recently enabled the identification of thousands of proteins in all cellular compartments as being lysine-acetylated in acute myeloid leukemia (AML) cells. The data revealed that the cytoskeleton appears to be highly affected by protein acetylation in AML cells, but how acetylation regulates protein-function remained unclear. To demonstrate the diverse regulative roles acetylation can perform, I will focus initially on studies on several specific proteins (short-term projects). Lysine-acetylation controls actin-nucleation and -polymerisation via hDia1, intracellular transport processes and protein-turnover of the small GNBP Ran, effector-binding of Cdc42, the functional Rho GTP/GDP cycle via RhoGEF2 and finally coordinates metabolic rates and cytoskeletal organisation as well as enzymatic activity of the glycolytic enzyme aldolase. Using the genetic-code expansion concept we want to incorporate acetyl-lysine and analyse the effect of acetylation in vitro and to study the consequences of protein lysine-acetylation on the cellular basis. Furthermore, in the mid-term we want to understand how acetylation itself is regulated. This includes identification of lysine deacetylases and – acetyltransferases for proteins, which were initially found to be functionally affected by lysine-acetylation. In the long-term quantitative proteomics using SILAC will give a detailed view of how the acetylation pattern of proteins change in ageing-associated dieseases as cancer and neurodegenerative disorders. If the change in the cytoskeletal acetylation pattern corresponds to altered protein activities and functionalities, this very likely supports development of ageing-associated processes as tumor-invasion and -metastasis. As a summary, we want to understand why so many proteins involved in cytoskeleton regulation are acetylated, how acetylation controls those activities and finally how the dysfunction of lysine-acetylation is a prerequisite for ageing-associated disorders. These studies will show the functional differences of lysine-acetylation compared to post-translational modifications as phosphorylation and ubiquitylation and may enable the development of new therapeutic strategies to treat ageing-associated dieseases.

赖氨酸 - 二乙酰酶抑制剂，乙酰 - 赖氨酸特异性抗体的可用性以及定量蛋白质的增强进展，使得在所有细胞隔室中的数千种蛋白质在急性髓样白血病（AML）细胞中被鉴定为所有细胞隔室中的数千种蛋白质。数据表明，细胞骨架似乎受AML细胞中蛋白质乙酰化的高度影响，但是乙酰化如何调节蛋白质功能仍然不清楚。为了证明乙酰化可以执行的潜水员常规作用，我最初将重点放在几种特定蛋白质（短期项目）的研究上。赖氨酸 - 乙酰化控制通过HDIA1，小gnbp运行的细胞内转运过程和蛋白质转变，cdc42的效应子结合，功能性Rho GTP/GDP循环通过Rhogef2和cylys cyly cyly cyly cyly cyly cylly cylly cymegentity Astosal assemaltity Astosal assemaltity Astosal的效应子结合，对cdc42的效应效应速率和蛋白质的结合均可对肌动症的速率进行效应，并与组织的cyly cyly cylly cyly cylly cylly cylys，酶藻酶。使用遗传代码膨胀概念，我们希望掺入乙酰赖氨酸并分析乙酰赖氨酸的作用，并分析乙酰赖氨酸在体外的影响，并研究蛋白质赖氨酸乙酰化对细胞基础的影响。此外，在中期，我们想了解乙酰乙酰化本身如何受到调节。这包括鉴定赖氨酸脱乙酰基酶和 - 乙酰转移酶的蛋白质，最初发现它们在功能上受赖氨酸 - 乙酰化的影响。在长期使用SILAC的长期定量蛋白质中，将详细了解蛋白质的乙酰化模式如何改变年龄相关的抑菌酶（如癌症和神经退行性疾病）。如果细胞骨架乙酰化模式的变化对应于改变的蛋白质活性和功能，那么这很可能支持与年龄相关的过程作为肿瘤侵袭和 - 自然的发展。总而言之，我们想了解为什么参与细胞骨架调节的众多蛋白质是乙酰化的，乙酰化如何控制这些活性，最后是赖氨酸 - 乙酰化的功能障碍是与老年相关疾病的前提。这些研究将表明赖氨酸乙酰化的功能差异与翻译后修饰相比，如磷酸化和泛素化，并可以开发出新的治疗策略来治疗与年龄相关的柴油酶。