Protein Folding | Chemical & Engineering News
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Web Date: August 13, 2008

Protein Folding

Molecular crowding causes disease protein to change shape
Department: Science & Technology
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THREE’S A CROWD
Increasing crowding causes VlsE to change from its native football shape (top) to bent-bean (middle) and spherical forms. The antibody-recognition site that becomes much more exposed in the spherical form is indicated in green.
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THREE’S A CROWD
Increasing crowding causes VlsE to change from its native football shape (top) to bent-bean (middle) and spherical forms. The antibody-recognition site that becomes much more exposed in the spherical form is indicated in green.

New findings on the effects of solution “crowding” on protein shape could help researchers better understand how proteins function in the jam-packed cellular environment.

Computer simulations and in vitro experiments on the football-shaped protein VlsE from the Lyme disease bacterium reveal that increased crowding by surrounding macromolecules causes the protein to change shape. The protein’s shape-shift is so dramatic that a hidden site recognized by antibodies used in Lyme disease diagnostics pops out like a jack-in-the-box. The work was done by Margaret S. Cheung at the University of Houston, Pernilla Wittung-Stafshede at Rice University, and coworkers (Proc. Natl. Acad. Sci. USA, DOI: 10.1073/pnas.0803672105).

“We propose that shape changes may be one way nature controls protein function, much like different facets can be exposed in an origami ‘cootie catcher,’ ” says Wittung-Stafshede, now at Umeå University, in Sweden. “It may be possible to develop targeted crowding as a precise tool to manipulate protein conformations to turn on or off specific activities and signaling cascades.”

In 1981, physical biochemist Allen P. Minton of the National Institute of Diabetes & Digestive & Kidney Diseases used a model system to first predict that crowding could cause elongated proteins to adopt more compact shapes. And other early studies showed that crowding could influence protein stability and folding speed. But the new study is the first to demonstrate crowding-induced shape changes in a large, biologically relevant protein. “I am pleased to see an experimental demonstration of the effect,” Minton says.

“What is new here is the idea that if a native protein has an elongated or nonspherical shape, then molecular crowding agents can selectively stabilize various states,” comments biophysics professor Ken A. Dill of the University of California, San Francisco. The study is “a significant extension of Minton’s early predictions,” and it shows that crowding “may have interesting biological relevance.”

Cheung, Wittung-Stafshede, and coworkers show that as crowding increases, VlsE converts from its native football shape to a bent-bean structure with additional α-helices. Then, at a level of crowding comparable with that in living cells, some of the α-helices change to β-sheet-like conformations, and the protein collapses to become spherical.

In the spherical state, an antibody-recognition site that had been largely hidden in the football and bent-bean forms becomes exposed on the outside of the protein. Until now, researchers didn’t understand how antibodies used in diagnostic tests for Lyme disease interacted with and recognized this site, which appeared inaccessible in crystal structures of native VlsE.

“Crowding and other environmental factors that affect protein shape may modulate protein function in cells,” says biological physicist José Onuchic of UC San Diego. “Much more is needed to demonstrate the feasibility of this effect,” but the study suggests a new mechanism cells may use to modulate protein function, he adds.

 
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