Spy infiltrates designer bacteria

U. MICHIGAN (US) — A newly-discovered molecular assistant has the capability to help bacteria excel at producing proteins for medical and industrial purposes.

Bacteria are widely used to manufacture proteins used in medicine and industry, but the bugs often bungle the job. Many proteins fall apart and get cut up inside the bacteria before they can be harvested and others collapse into useless tangles instead of folding properly, as necessary in order to function normally.

Researchers figured out how to coerce bacteria into making large quantities of stable, functional proteins—and then while exploring why the designer bacteria were so successful, discovered the molecular helper, Spy.

“It is exciting to realize that if even bacteria are asked in the right way, they can come up with good solutions to hard problems,” says postdoctoral fellow Shu Quan, who spearheaded the work, led by James Bardwell, professor of molecular, cellular, and developmental biology and of biological chemistry, at the University of Michigan.

The research is reported online in the journal Nature Structural & Molecular Biology.

In the first phase of the study, researchers designed biosensors that directly link protein stability to the antibiotic resistance of bacteria. When a poorly folded, unstable protein is inserted into the middle of the biosensor in a bacterium, it disrupts the bug’s resistance to antibiotics. When the protein is stabilized, resistance is restored.

A particularly unstable protein was inserted into Escherichia coli (E. coli), which forced the bacteria to either adapt by improving protein stability or die when exposed to antibiotics.

Through a “directed evolution” experiment, in which the scientists selected colonies with increasing antibiotic resistance—and increasing protein stability—designer bacteria was generated that produced up to 700 times more of the previously unstable protein.

In looking to see why the designer bacteria were so much better at producing proteins, the scientists found that the efficient microbes were making much more of a small protein called Spy.

The cradle-shaped Spy aids in protein refolding and protects unstable proteins from being cut up or sticking to other proteins.
“Our work may usher in an era of designer bacteria that have had their folding environment customized so that they can now efficiently fold normally unstable proteins,” Bardwell says.

Researchers at McGill University contributed to the study, that was funded by the Howard Hughes Medical Institute and the Canadian Institutes of Health Research.

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