Translational Control: Discovery and Mechanisms

安德烈·A·科罗斯特列夫 摘要 核糖体是控制基因表达的中心枢纽。它们不仅合成蛋白质，而且还调节 细菌应激反应、人类神经发育和突触可塑性。了解核糖体如何 控制基因的表达需要高分辨率的结构和准确的生化表征 体外和复杂细胞环境中的核糖体动力学和相互作用。我们独一无二 通过调查以下问题来应对这些关键挑战： 核糖体如何调节细菌的应激反应？在细菌中，核糖体通过 控制转录适应压力的几条途径。直接和间接的途径， 将翻译和转录结合起来是很有希望的抗生素靶点。我们将解剖结构和细胞 使用新的生化方法和集成低温EM的机制。 核糖体如何感知功能和功能失调的mRNAs？翻译是翻译的主要途径 在真核生物中感知有问题的mRNAs，以及应激反应机制的失调导致疾病。 为了确定核糖体如何识别带有早熟无义密码子的功能失调的mRNAs，我们将使用 显示核糖体与核糖体相互作用的细胞、生化和结构(时间分辨低温电子显微镜)方法 有问题的mRNA。 翻译如何调节神经发育和神经可塑性以及对神经学的贡献 精神障碍？神经元的翻译调节对神经发育、记忆巩固和 学习，而翻译失调会导致神经系统疾病，如肌萎缩侧索硬化症。 远离细胞核的突触蛋白质组由局部翻译控制，需要特定于大脑的蛋白质组 翻译因子和辅助蛋白。阐明神经元翻译的分子机制 在监管方面，我们将使用遗传、生化和结构方法，包括在恩斯特罗姆一级的细胞EM 功能神经元的细节。

Andrei A. Korostelev ABSTRACT Ribosomes are a central hub for controlling gene expression. They not only synthesize proteins, but also regulate bacterial stress responses, human neurodevelopment and synaptic plasticity. Understanding how ribosomes control gene expression requires high-resolution structural and accurate biochemical characterization of ribosome dynamics and interactions, both in vitro and in complex cellular environments. We are uniquely positioned to address these key challenges by investigating the following questions: How do ribosomes regulate bacterial stress responses? In bacteria, ribosomes sense cellular stress via several pathways, which control the transcriptional adaptation to stress. The direct and indirect pathways that couple translation with transcription are promising antibiotic targets. We will dissect the structural and cellular mechanisms of using novel biochemical approaches and ensemble cryo-EM. How do ribosomes sense functional and dysfunctional mRNAs? Translation is a major pathway for sensing problematic mRNAs in eukaryotes, and dysregulation of stress-response mechanisms leads to disease. To determine how the ribosome recognizes dysfunctional mRNAs with premature nonsense codons, we will use cellular, biochemical and structural (time-resolved cryo-EM) methods to visualize ribosome interactions with problematic mRNAs. How does translation regulate neurodevelopment and neuroplasticity and contribute to neurological disorders? Translation regulation in neurons is essential for neurodevelopment, memory consolidation, and learning, whereas translation dysregulation drives neurological diseases, such as amyotrophic lateral sclerosis. The synaptic proteome—far from the nucleus—is controlled by local translation and requires brain-specific translation factors and auxiliary proteins. To elucidate the molecular mechanisms of neuronal translation regulation, we will use genetic, biochemical, and structural approaches, including cellular EM at Ångström-level detail in functional neurons.