Proteasomes are large multi-subunit complexes, localized in the nucleus and cytosol that selectively degrade intracellular proteins. The ubiquitin-proteasome pathway plays a major role in the degradation of many proteins involved in cell cycle, proliferation, and apoptosis. Proteasomes also breakdown abnormal proteins that result from oxidative stress and mutations that might otherwise disrupt normal cellular homeostasis. This pathway has been implicated in several forms of malignancy, in the pathogenesis of several genetic diseases, and in the pathology of muscle wasting. It is also involved in the destruction of proteins that participate in cell cycle progression, transcription control, signal transduction, and metabolic regulation. A protein marked for degradation is covalently attached to multiple molecules of ubiquitin (Ubq), a highly conserved 76-amino acid (8.6 kDa) protein, which escorts it for rapid hydrolysis to the multi-component enzymatic complex known as the 26S proteasome. The proteolytic core of this complex, the 20S proteasome, contains multiple peptidase activities and functions as the catalytic machine. This core is composed of 28 subunits arranged in four heptameric, tightly stacked, rings (a7, b7, b7, a7) to form a cylindrical structure. The a-subunits make up the two outer and the b-subunits the two inner rings of the stack. The entrance of substrate proteins to the active site of the complex is guarded by the a-subunits that allow access only to unfolded and extended polypeptides. The proteolytic activity is confined to the b-subunits.
In the ubiquitin-proteosome degradation pathway, Ubq is first covalently ligated to target proteins by a multi-enzymatic system consisting of Ubiquitin-activating (E1), Ubiquitin-conjugating (E2), and the Ubiquitin-ligating (E3) enzymes. The E1 activates a Ubiquitin monomer at its C-terminal cysteine residue to a high-energy thioester bond which is then transferred to a reactive cysteine residue of the E2 enzyme. The final transfer of ubiquitin to e-amino group of a reactive lysine residue of substrate proteins is brought about by the E3 enzyme. Ubiquitinated protein is then escorted to the 26S proteasome where it undergoes final degradation and the ubiquitin is released and recycled.
References:
Magill, L., et al. 2003. Hematology 8, 275.
Voorhees, P.M., et al. 2003. Clin. Cancer Res. 9, 6316.
Kroll, M., et al. 1999. J. Biol. Chem. 274, 7941.
Koegl, M., et al. 1999. Cell 96, 635.
Schwartz, A.L., and Ciechanover, A. 1999. Annu. Rev. Med. 50, 57.
Gerards, W.L.H., et al. 1998. Cell. Mol. Life Sci. 54, 253.
Spataro, V., et al. 1998. Br. J. Cancer 77, 448.
Jensen, D.E., et al. 1998. Oncogene 16, 1097.
Pickart, C.M. 1997. FASEB J. 11, 1055.
Bogyo, M., et al. 1997. Biopolymers 43, 269.
Coux, O., et al. 1996. Annu. Rev. Biochem. 65, 801.
Maupin-Furlow, J.A., and Ferry, J.G. 1995. J. Biol. Chem. 270, 28617.
Jensen, T.J., et al. 1995. Cell 83, 129.
Ciechanover, A. 1994. Cell 79, 13.
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