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Synthetic Biology

Artificial organelles are designed for protein engineering

Phase separation sequesters the machinery for repurposing stop codons

by Celia Henry Arnaud
March 30, 2019 | APPEARED IN VOLUME 97, ISSUE 13

 

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Credit: Adapted from Science
Inside the designer organelle (light blue), nonnatural amino acids can be added during protein synthesis at the location of the Amber stop codon. Outside the organelle, the stop codon still halts protein synthesis.

Designer organelles might make it easier to produce engineered proteins in mammalian cells. Edward A. Lemke of the Johannes Gutenberg University Mainz’s Institute of Molecular Biology and the European Molecular Biology Laboratory and his coworkers have made artificial membraneless organelles from “assemblers” that are hybrids of truncated motor proteins that assemble on microtubules and proteins that phase separate above a minimum concentration (Science 2019, DOI: 10.1126/science.aaw2644). The two types of proteins assemble into structures that allow the simultaneous spatial and phase separation of the machinery needed for synthesizing proteins with nonnatural amino acids. That machinery includes the suppressor transfer RNA and tRNA synthetase needed for repurposing the Amber stop codon—a signal for cells to stop protein translation—as one that inserts nonnatural amino acids into proteins. The researchers also add a tag that steers the target messenger RNA to the organelle. This strategy enables the researchers to target specific Amber stop codons without affecting the others found in mammalian cells. They used the system in cultured human kidney cells. Biologists have worried that indiscriminate suppression of Amber stop codons could make “weird things happen,” Lemke says. “We have conceptually solved the toxicity/specificity problem of Amber suppression.” In the future, Lemke wants to use smaller phase-separating proteins to make the system even less invasive. He also plans to make other types of artificial organelles that perform novel functions in semisynthetic organisms.

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