Translational Control: Discovery and Mechanisms

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.