Stem Cells 2003;21:509-510
www.StemCells.com
© 2003 AlphaMed Press
Fundamentals of Cancer Medicine |
The Molecular Perspective: Ubiquitin and the Proteosome
David S. Goodsell
David S. Goodsell, Ph.D., Associate Professor, The Scripps Research Institute, Department of Molecular Biology, 10550 North Torrey Pines Road, La Jolla, California 92037, USA. Telephone: 858-784-2839; Fax: 858-784-2860; e-mail: goodsell{at}scripps.edu Website: http://www.scripps.edu/pub/goodsell
The cell is a busy place, with thousands of processes occurring simultaneously. Cells coordinate this action, among other ways, by passing protein messages from site to site. These messages are part of a complex bureaucracy that controls day-to-day actions of the cell. When key messages that direct cellular growth are disrupted, cancer can be the result.
As you might expect, these protein memos are delivered and read immediately, and then they quickly become obsolete. They must be destroyed, making ready for the next messenger, which often carries exactly opposite instructions. The proteosome has the job of destroying obsolete messages, as well as a host of other short-lived protein machinery. The proteosome is a protein shredder. At its heart is a tube of 28 proteins with protein-cutting machinery on the inside. Proteins are fed through the tube and cut into small peptides, which are then rapidly cut into individual amino acids by other peptidases and recycled to build new proteins.
The presence of an efficient protein shredder in the cell is potentially disastrous. After all, the cell is filled with proteins. So, the proteosome must be carefully controlled. A selective doorway is placed at each end of the shredder, which only allows entry to those proteins that are ripe for destruction. It would be difficult, however, to design a doorway that correctly recognizes the hundreds of different proteins that are scrapped daily by the proteosome. So instead, the cell adds an intermediate step. First, obsolete proteins are identified and tagged, then these tagged proteins are shipped off to the proteosome.
Obsolete proteins are tagged using the small protein ubiquitin, so named because it is found in nearly identical form in most organisms. Many different proteins are destroyed by the proteosome when they are no longer needed, including signaling proteins, enzymes, and structural proteins. A host of dedicated ubiquitin-protein ligase enzymes seek out obsolete proteins and attach ubiquitin to their surfaces. To make the signal even more obvious, these enzymes actually attach a chain of several ubiquitin molecules, as shown in Figure 1
. The proteosome recognizes proteins with this chain of ubiquitin molecules and pulls them into its active site. There, they are unfolded and fed through the shredding chamber.
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Figure 1. Ubiquitin proteins are added to an obsolete protein (Src protein in this picture), tagging it for destruction by the proteosome. Atomic structures were taken from entries 1f9j
[PDB]
and 2src
[PDB]
from the Protein Data Bank (http://www.pdb.org).
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Problems occur when different aspects of this system are compromised. As shown in Figure 2, a viral protein can interfere, causing an enhanced destruction of the p53 tumor suppressor and making infected individuals more susceptible to tumor growth. Alternatively, a protein messenger may be unnaturally protected from destruction, so it will send its signal for too long a period of time. This is the case with the Jun transcription factor. The normal cellular form of Jun is sensitive to degradation and thus only performs its job for a short period of time. A viral version, on the other hand, is insensitive to the enzymes that add ubiquitin. As its levels rise unnaturally, its continual presence can transform cells.
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Figure 2. The proteosome in action. At the top, the p53 tumor suppressor (the many-armed protein in yellow) is being tagged for destruction. Two specific enzymes (shown in orange) are recognizing one of the upper arms of the protein and adding ubiquitin (shown in red). The small purple protein assisting with this addition is E6 from papillomavirus. It artificially enhances the connection of ubiquitin to p53, leading to unnaturally low levels of p53 in infected cells. Two of the lower arms in the p53 molecule have strings of ubiquitin attached and are ready for processing by the proteosome. The proteosome is a large protein complex, shown here at the bottom in red. The protein destruction machinery is inside the tube at the center of the complex, and the large domains on each site, composed of dozens of proteins, control entry of ubiquitin-tagged proteins.
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ADDITIONAL READING-
Glickman MH, Ciechanover A. The ubiquitin-proteosome proteolytic pathway: destruction for the sake of construction. Physiol Rev 2001;82:373–428.
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Pickart CM. Ubiquitin in chains. Trends Biochem Sci 2000;25:544–548.[CrossRef][Medline]
