QBI presents a seminar with Jonathan Patrick Schlebach, Associate Professor in the Department of Chemistry at Purdue University. Research in the Schlebach lab is focused on the biochemical and biophysical aspects of integral membrane protein biosynthesis, folding, and misfolding in the cell. Dr. Schlebach's laboratory utilizes an interdisciplinary array of biochemical, cellular, and computational techniques in order to gain mechanistic insights into the key reactions that modulate cellular protein homeostasis and to determine how they factor into the molecular mechanisms of evolution and disease. They are also adapting these tools and perspectives to develop and target new precision therapeutics for various genetic diseases including cystic fibrosis, retinitis pigmentosa, and cerebral creatine deficiency syndrome.

Talk Title: Cotranslational Assembly Defects Trigger a Proteostatic Killswitch in the Ribosome

Though the ribosome possesses several features that help maintain its translational reading frame, certain transcripts contain RNA structures that override these mechanisms to promote ribosomal frameshifting. Dr. Schlebach's group recently found that conformational transitions in the nascent polypeptide can also enhance the activity of a viral RNA structure that stimulates -1 programmed ribosomal frameshifting (-1PRF). However, it remains unclear whether the nascent chain plays a more general role in translational fidelity. In this work, they demonstrate that the features of nascent polypeptides alone are capable of triggering efficient -1PRF, which typically results in the premature termination of translation. They provide evidence that cotranslational feedback between nascent chains, translocons, and ribosomes allows the translational machinery to terminate protein synthesis in response to misfolding of the nascent chain or the incorrect splicing of a transcript. Their findings suggest feedback between the nascent chain and ribosome may play a more general role in the negative regulation of translation.

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