Accurate protein synthesis is fundamental to organismal biology. Dysregulation of proteostasis leads to human pathologies including neurodegeneration, aging, cardiac disease, and macular disorders. Ribosomes are the critical machinery responsible for synthesis of correctly decoded, functional proteins. The active site of the ribosome is composed of a catalytic ribosomal RNA center which is evolutionarily conserved among all life. Despite its importance, how to optimize accurate protein synthesis remains a key gap in our knowledge of ribosome function and presents an opportunity to target proteostatic disease. We have used comparative biology, biochemistry, cryo-EM, and genetics to identify how evolution of ribosomal RNA can increase accuracy of protein synthesis. Altogether, our work provides fundamental insights into how protein synthesis machinery has evolved variant activities and why this leads to unique organismal phenotypes. Our long-term goal is to leverage these findings to develop novel ribosome-targeting methods to address devastating proteostatic human diseases.
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