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Popot Uses Amphipols to Enable Membrane Protein Studies

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Scientists have nailed down a technique to capture membrane proteins and study them in their native state, according to research published recently in PNAS. In work from the University of Copenhagen and National Center for Scientific Research in Paris, researchers used synthetic polymers called amphipols to extract and immobilize functional, unmodified membrane proteins. Two prime applications for this method include improved high-throughput screening for drug compounds and protein microarrays.

Membrane proteins, which make up about one-third of the proteome, span the entire lipid cellular membrane and are highly hydrophobic. Typically, they're isolated using detergents. However, says lead author Jean-Luc Popot, detergents can interact with the protein in such a way that its native structure is disturbed. "The bottom line is that membrane proteins in detergent solutions are usually marginally stable," he says. "For many years we have thought that replacing the detergents with amphipathic polymers could be a way around this problem." Indeed, after 14 years of work, he's finally resolved a method to bind the synthetic polymer to the protein in such a way that the protein is water soluble, stabilized, and functional for immobilization onto chips or beads.

While amphipols have been used for many years to stabilize inks and paints, "what is new is that we have designed [them] so that they are very short and are densely covered with hydrophobic chains," Popot says. In this way, they can form complexes with membrane proteins. "So now you have a complex which is water soluble in which the protein is stable, and this complex is permanent." Amphipols are also rather large at about 10 kDa, so modifying the complex with a molecule like biotin won't change the physical or chemical properties of the amphipol.

"So it's a very nice way to label the protein indirectly but permanently," Popot says. "You don't have to modify the protein -enetically; you don't have to modify it chemically. What you do is you covalently modify the amphipol, the amphipol sticks to the protein, and thereby it associates whatever you've bound to the amphipol to the protein."

One way to make use of these complexes is by attaching them to a coated surface, like a bead or chip, which binds biotin. Testing for competitive drug binding targets is one high-throughput screen that could be run, while testing serum for the existence of antibodies to a particular antigen is another.

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