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Coloring Outside the Proteins

08/12/2014
Kayt Sukel

Can the addition of some extra color help scientists understand how proteins interact in real time? Find out...


Understanding the etiology and progress of disease requires understanding how proteins interact to send important biological signals across the body. But so far, even technologically advanced methods such as computer modeling have been unable to demonstrate how proteins make contact in real time. To solve this problem, Lance Liotta, co-director of George Mason University’s Center for Applied Proteomics wondered if perhaps an old-school method like staining might help scientists better understand how proteins work together.

Protein painting reveals solvent-excluded drug targets (1)

“There are a lot of dyes out there that are used in staining histology, as you can imagine, and pathology histology. There are also stains and dyes that stain fabrics and those that are used in printing and xerography,” said Liotta, a pathologist by training. “But almost none of them have been studied for their ability to bind to proteins. So we got our hands on all kinds of different dye chemistries and looked at how they bind to those proteins. And that led to the idea of protein painting.”

The group found that by “painting” proteins with common printer dyes, they were able to see where two proteins touch, illuminating what scientists call the “hot spot.”

“This is something that just in one step gives us the sequence of the regions where two or more proteins touch each other,” said Liotta. “And that’s important because those interfaces are the drug targets of the future. In the past, drugs have been designed to block enzymes or enzyme substrates. But in protein/protein interactions, there’s no enzyme most of the time. You just have to try to keep them from sticking together and find a way to block the area where they touch.”

As proof of concept, Liotta and colleagues dyed proteins in the interleukin signaling pathway, which plays an important rolfe in inflammation, cancer, and neurodegenerative disease. The researchers were then able to find points of interaction against which they created two inhibitors, a peptide and an antibody, that blocked the protein connection—and therefore blocked the inflammation signals that often get out of whack in disease states.

“And this is a technique that is low cost that any mass spectrometry lab can do,” said Liotta. “Our overall goal is moving beyond just measuring signaling in the cell or measuring biomarkers. We want to develop new therapeutics, and protein/protein interaction is a very important area where we can find those new therapeutics.”

Reference

Luchini A, Espina V, Liotta LA. Protein painting reveals solvent-excluded drug targets hidden within native protein-protein interfaces. Nat Commun. 2014 Jul 22;5:4413.

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