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Bacterial machinery tracks the shape and quality of proteins

Tuesday, August 7, 2012

DeLisa Research Group

The DeLisa lab has discovered that bacteria possess built-in machinery that tracks the shape and quality of proteins trying to pass through their cytoplasmic membranes. The work is detailed in the Proceedings of the National Academy of Sciences, July 30. The quality-control mechanism discovered by DeLisa and coworkers is embedded in the machinery of the twin-arginine translocation (Tat) pathway, which is a protein export pathway in plants, bacteria and archaea. The transport of proteins across cellular membranes is a basic life process and understanding how the Tat pathway works could lend insight into, for example, how bacteria become resistant to antibiotics. The Tat pathway is remarkable because, unlike other similar processes, the protein cargo passes through the cell membrane in tightly folded shapes, as opposed to long strings. The pathway allows properly folded proteins to pass, while badly folded or damaged ones are not permitted through. DeLisa and colleagues Mark Rocco, a graduate student, and Dujduan Waraho-Zhmayev, a postdoctoral associate, used an old trick to make this new discovery:

They set up a genetic selection experiment that enables researchers to link genetic mutations to the survival of a cell carrying that mutation.

Using a genetic selection for Tat export, they were able to isolate a mutation known as a suppressor in the Tat machinery that allowed the bacteria to survive if they exported misfolded proteins. They concluded that the bacteria's survival was attributed to their ability to export misfolded proteins, which normal bacteria in nature wouldn't do. The team's findings provide the first direct evidence for the participation of the Tat machinery in regulating the export of proteins. The Tat machinery, they speculate, contains a component that senses whether a protein is folded properly and discriminates between folded or unfolded proteins, allowing export of only the well-folded ones. The team's new insight into how the Tat pathway regulates the quality of proteins should be useful for many biotechnology applications including, for example, the hunt for 'good' antibodies that bind specifically to their target and are very well behaved from a folding standpoint. The research was supported by National Institutes of Health and the National Science Foundation.

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