Ubiquitin/Proteasome

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• Reviews
• Pathway Key
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Pathway Description:

The ubiquitin proteasome pathway, conserved from yeast to mammals, is required for the targeted degradation of most short-lived proteins in the eukaryotic cell. Targets include cell cycle regulatory proteins, whose timely destruction is vital for controlled cell division, as well as proteins unable to fold properly at the endoplasmic reticulum.

Ubiquitin modification is an ATP-dependent process carried out by three classes of enzymes. A “ubiquitin activating enzyme” (E1) forms a thio-ester bond with ubiquitin, a highly conserved 76 amino acid protein. This reaction allows subsequent binding of ubiquitin to a “ubiquitin conjugating enzyme” (E2), followed by the formation of an isopeptide bond between the carboxy-terminus of ubiquitin and a lysine residue on the substrate protein. The latter reaction requires a “ubiquitin ligase” (E3). E3s can be single- or multi-subunit enzymes. In some cases, the ubiquitin-binding and substrate-binding domains reside on separate polypeptides brought together by adaptor proteins or cullins. Numerous E3s provide specificity in that each can modify only a subset of substrate proteins. Further specificity is achieved by post-translational modification of substrate proteins, including but not limited to phosphorylation.

Effects of monoubiquitination include changes in subcellular localization. However, multiple ubiquitination cycles resulting in a polyubiquitin chain are required for targeting a protein to the proteasome for degradation. The multisubunit 26S proteasome recognizes, unfolds and degrades polyubiquitinated substrates into small peptides. The reaction occurs within the cylindrical core of the proteasome complex, and peptide bond hydrolysis employs a core threonine residue as the catalytic nucleophile.

Recent work has indicated that an additional layer of complexity, in the form of multiubiquitin chain receptors, may lie between the polyubiquitination and degradation steps. These receptors react with a subset of polyubiquitinated substrates, aiding in their recognition by the 26S proteasome and thereby, promoting their degradation.

This pathway is not only important in cellular homeostasis, but also in human disease. Because ubiquitin/proteasome-dependent degradation is often employed in control of the cell division cycle and cell growth, proteasome inhibitors are currently under investigation as cancer therapeutic agents. Furthermore, accumulation of misfolded proteins may contribute to some neurodegenerative diseases.

Selected Reviews:

• Adams J (2004) The development of proteasome inhibitors as anticancer drugs. Cancer Cell 5(5), 417–21.
• Hartmann-Petersen R, Gordon C (2004) Protein degradation: recognition of ubiquitinylated substrates. Curr. Biol. 14(18), R754–6.
• Pickart CM (2004) Back to the future with ubiquitin. Cell 116(2), 181–90.
• Verma R, Oania R, Graumann J, Deshaies RJ (2004) Multiubiquitin chain receptors define a layer of substrate selectivity in the ubiquitin-proteasome system. Cell 118(1), 99–110.

created September 2004 • revised February 2007