Sharing MCB Science: Protein synthesis by ribosomes with tethered subunits

Cells are known as the basic building blocks of life. They contain a vast number of highly specialized components to carry out the wide array of cellular functions. The ribosome is the central component responsible for protein synthesis. Previously we assumed that the ability of the two ribosomal subunits to separate from each other was required for successful protein synthesis. This assumption is now known to be inaccurate.

Dr. Michael C. Jewett, Associate Professor of Chemical and Biological Engineering at Northwestern University, and Dr. Alexander Mankin, Director of the University of Illinois Chicago’s College of Pharmacy’s Center for Biomolecular Sciences, and their colleagues have constructed a ribosome with covalently tethered subunits (dubbed “Ribo-T”). Specifically, Jewett and Mankin have engineered a ribosome where the ribosomal RNA is shared between the two subunits and linked by small RNA tethers. Dr. Mankin describes this as “two different people holding hands.” He explains, ” We have created ribosomes that can’t let go of their hands.”

This new finding leads to two different scenarios. First, these new ribosomes, or Ribo-T, are able to sustain the life of a cell without the presence of naturally occurring ribosomes. In the other scenario, Ribo-T can be used to create a ribosome mRNA system where mRNA decoding, catalysis of polypeptide synthesis and protein excretion can be optimized for new substrates and functions. This could transform the field of biomolecular engineering and synthetic biology. For example, Ribo-T can be used to explore poorly understood functions of the ribosome (e.g., antibiotic resistance mechanisms, a rising global health issue), to enable orthogonal genetic systems, or to engineer ribosomes with altered chemical properties (e.g. ribosomes that are more efficient at using non-natural amino acids). Jewett said, “a lot of people consider the ribosome to be the chef of translation and so one of the things we’re curious to know now is if you have the ability to make specialized chefs, chefs that make different types of cuisines, what kind of chefs would you make? Put another way, could we evolve the ribosome to perform new types of chemistry?” The findings of this research are described in a research article recently published in Nature.

When asked about the broader impacts of this experiment, Dr. Jewett responded:

“I view Ribo-T as a new protein-making factory, version 2.0. I think it holds promise to really expand the genetic code and our ability to produce useful molecules for society in a unique and transformative way. Our advance enables us to imagine repurposing the normal protein synthesis machinery in cells to make products that have not been possible before. This new protein synthesis is natural, but engineered. Now we open ourselves to a new world, having an expanded chemistry of living systems where we are not limited to the common building blocks.”

Dr. Jewett also added, “One of the most exciting things about this adventure is that it celebrates interdisciplinary science. The research was high-risk and a lot of people suggested that it didn’t work. Our collaborators in the Mankin lab have been phenomenal and the first authors, Erik Carlson (in my group) and Cedric Orelle were spectacularly courageous. Fortunately, we were able to use evolution in the context of engineering design to find a winner. I honestly think it is one of the reasons we were able to crack the code.”

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