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A Protein’s Path to the “Chamber of Doom”

Researchers have uncovered a perilous pathway within the cell that rivals any road taken by Indiana Jones or his summer blockbuster companions: a slippery tube that funnels proteins into a “chamber of doom” where they are shredded and recycled into the building blocks of new proteins.

The tube is part of the 26S proteasome, an enzyme that acts as the cell’s protein garbage disposal. As described by researchers from the Technion-Israel Institute of Technology and the University of Texas Health Science Center at San Antonio, the tube is a concentric stack of rings wrapped in molecular motors that speed the proteins toward the proteasome’s slicing and dicing core.

“The life of all proteins in our cells ends within the proteasome chamber of doom,” Technion author Michael Glickman explained. He suggested that the newly-described pathway “should be of interest in applications for diseases in which cells are unable to process degraded or misfolded proteins,” including Alzheimer’s and Parkinson’s disease, some cancers, and age-related conditions such as cataract disease.

The study, published online in June in the journal Nature Structural and Molecular Biology, will help researchers understand the basic biology of the proteasome and “its intrinsic essential function in a myriad of cellular pathways,” said Allen Taylor, who has studied proteasome function extensively as director of the Laboratory for Nutrition and Vision Research at Tufts University.

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The 26S proteasome degrades proteins that are marked for destruction with a ubiquitin protein “tag.” The proteasome itself consists of two major structures: a large core structure where the proteins are degraded, and a smaller structure that serves as a kind of entryway where the tagged protein makes its first contact with the proteasome and is unfolded for its journey into the core. The tube described by Glickman and colleagues is part of the smaller structure, and serves a chute between the first contact site and the core.

The researchers used atomic force microscopy to visualize the extremely tiny tube, which Glickman described as two molecular “donuts” stacked on top of each other. The donut holes through which proteins pass is only two nanometers in diameter. (For comparison, the period at the end of this sentence is one million times wider than a nanometer.)

The tube is ringed by a group of energy-producing enzymes called ATPases, which act a motor to drive proteins through the tube. “One may see the entire machine as an external engine wrapping around an inner molecular stent for protein translocation, all situated atop the molecular shredder into which the proteins are fed,” Glickman explained.

It’s a natural design that engineers working on synthetic nanomachines might hope to copy in their own creations, he noted.

The Technion-Israel Institute of Technology is Israel's leading science and technology university. Home to the country’s winners of the Nobel Prize in science, it commands a worldwide reputation for its pioneering work in nanotechnology, computer science, biotechnology, water-resource management, materials engineering, aerospace and medicine. The majority of the founders and managers of Israel's high-tech companies are alumni. Based in New York City, the American Technion Society (ATS) is the leading American organization supporting higher education in Israel, with 22 offices around the country.

Kevin Hattori | Newswise Science News
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