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Biological Chemistry

Designer Ribosome Works In Live Cells

Synthetic Biology: Researchers engineer entire protein-making complex for first time

by Stu Borman
July 30, 2015 | APPEARED IN VOLUME 93, ISSUE 31

Credit: Nature
Two polyadenine RNA tethers (red) link Ribo-T’s two engineered ribosomal subunits, small (left) and large (right).
Credit: Nature
Two polyadenine RNA tethers (red) link Ribo-T’s two engineered ribosomal subunits, small (left) and large (right).

Researchers have artificially engineered a complete ribosome—the cell-based machine that translates mRNA into proteins—in the laboratory.

The ability to engineer the ribosome not only could help scientists understand how the protein-maker works, but it also could endow the ribosome with new functions. For drug discovery and basic research, engineered ribosomes could create nonnatural proteins or even nonprotein polymers that would be difficult or impossible for native ribosomes to make.

Alexander Mankin of the University of Illinois, Chicago; Michael C. Jewett of Northwestern University; and colleagues designed, engineered, and characterized the artificial ribosome, which they call Ribo-T (Nature 2015, DOI: 10.1038/nature14862).

“It’s an impressive body of work that will enable the directed or random evolution of ribosomes with modifications that allow synthetic amino acids to be more efficiently incorporated, or even to expand the genetic code,” comments ribosome assembly specialist Katrin Karbstein of Scripps Research Institute Florida.

Ribosomes have two independent parts, small and large subunits, which come together in cells to form a complete structure when protein translation is needed. Small ribosomal subunits that make a specific protein have been prepared by genetic engineering before, but not the entire ribosome.

Mankin, Jewett, and coworkers made Ribo-T by engineering ribosomal RNAs, the main components of the small and large subunits, into a single hybrid gene that included two short polyadenine RNA linkers to connect the RNAs. Then the team introduced the modified gene into bacteria. The bacterial cells transcribed the gene into tethered ribosomal RNAs, which then joined with ribosomal proteins made by the cells to form the complete ribosome.

Ribo-T can replace all of a bacterium’s natural ribosomes, can express all native proteins in the bacterial genome, and works nearly half as fast as native ribosomes—fast enough to sustain normal cell growth and proliferation. The researchers also demonstrated that it could be engineered to make a protein with an amino acid sequence native ribosomes can’t handle.

Scientists previously believed that, for ribosomes to work properly, their two subunits had to be independent and had to come together only when needed. But Ribo-T, with its linked subunits, seems to disprove that.

Ribo-T “is a long-sought platform for exploring the mechanism of protein synthesis,” comments ribosome mechanism expert Jamie H. D. Cate of the University of California, Berkeley.

Mankin, Jewett, and coworkers want to use Ribo-T to explore poorly understood ribosome functions and make novel protein-based agents for drug discovery and other applications. “Our new protein-making factory holds promise to expand the genetic code in a unique and transformative way,” Jewett says.



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Inweregbulam U . Emmanuel (July 31, 2015 7:16 AM)
In deed this is exciting area of research. The insights acquired through this artificial ribosomes will scientists understand among others, the mechanism of protein synthesis and how the submits of the cell factory orient themselves in the course of their work within the cell.
Scott C. Mohr (August 5, 2015 2:39 PM)
What an amazing accomplishment -- that holds great promise for expanding the synthetic biology repertoire! Labs all over will be trying this out on some of the great variety of ribosome types and it suggests that similar approaches to other macromolecular machines may also succeed. This would mean that the repertoire of "off-the-shelf" components available to engineer new types of cells might expand much more rapidly rapidly and with greater variety than anyone would have previously thought. Among other things, **this means that vigorous efforts need to be made at once to provide for safety and security as synthetic biology roars ahead!""

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