Beset by peers trying to tear them apart, proteins known as proteases constantly risk destruction. UCSF scientists have determined how a nearly impregnable design protects some of the most besieged proteases, a design that contradicts a basic assumption of chemistry.
The UCSF team studied alpha-lytic protease, a protein that breaks down nutrients for bacteria in the soil, an unforgiving environment where hundreds of protease species slash at each other. They found that the alpha-lytic protease is about 100 times more resistant to attack by other proteases than are digestive enzymes or other conventional proteases.
The key to this toughness, the scientists discovered, is the novel way the protease is folded into working order, a process fundamentally different from the effortless way most proteins fold into action and one that requires more energy at the outset but achieves remarkable stability.
They suspect this design strategy is mimicked in other environments extremely vulnerable to protease destruction, including lysosomes in human cells, where proteins are broken down for recycling.
The UCSF research is published in the January 17 issue of the journal Nature.
Most proteins -- made of linear chains of amino acids fold spontaneously into their working configuration, a shape that represents their most relaxed condition -- their lowest energy state. They occasionally unfold to some degree and then refold -- "breathing" as chemists call it. Whenever they do unfold, proteins risk attack by proteases designed to tear at newly exposed regions.
But the alpha-lytic protease does not spontaneously fold into a ready-to-work shape. It must be bent into working condition by a catalyst that temporarily becomes part of the molecule and is known as the pro-region. The UCSF researchers found that the structure sculpted by the pro-region is remarkably resistant to unfolding. Whereas normal proteins transiently unf
Contact: Wallace Ravven
University of California - San Francisco