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The unfolding force is constant over time. Sauer/Elsevier

Before destroying proteins, proteases such as bacterial ClpXP and the related eukaryotic proteasome must denature them. Jon Kenniston, Robert Sauer (MIT, Cambridge, MA), and colleagues now show that ClpX denatures by repeatedly applying a uniform unfolding force. "The way the enzyme works is to keep trying," says Sauer.

This strategy works because proteins fluctuate around an average structure over time. Even a very stable protein will, very infrequently, be surprised in a relatively susceptible state. When this happens, the standard pulling force by ClpX is enough to unravel the protein. The enzyme then quickly threads the denatured protein through a narrow hole, toward the protease active site, before the substrate can refold.

The MIT group discovered the repetitive pulling phenomenon by studying stability variants of the muscle protein titin. This allowed "us to deconvolute how much ATP hydrolysis is used for unfolding versus translocating," says Sauer.

During denaturation of different variants, the ATP hydrolysis rate was constant, but the amount of time taken to denature varied widely. Thus, although unstable variants were destroyed by a handful of ATP cycles, the destruction of a wild-type titin domain took more ATP molecules than were used in the protein's biosynthesis.

When it fails, the ClpX unfoldase probably lets the pulling process cycle back to a ground state. This slipping may be inevitable given the protein's construction. "The enzymes aren't very stable proteins by themselves, so we don't think they have any way to store energy," says Sauer. For that reason, he says, "there's no way of making unfolding a cumulative process."

Reference:

Kenniston, J.A., et al. 2003. Cell. 114:511–520.[CrossRef][Medline]

William A. Wells

wellsw{at}rockefeller.edu

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This Article PDF (Full Text) PPT slides of all figures Alert me when this article is cited Services Email this article Similar articles in this journal Alert me to new content in the JCB Download to citation manager Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Wells, W. A. Search for Related Content PubMed Articles by Wells, W. A. Social Bookmarking                      What's this?