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泛素-蛋白酶体途径

Sino Biological offers a comprehensive set of tools for the study of ubiquitin-proteasome pathway, including recombinant proteins, antibodies (rabbit mAbs, mouse mAbs, and rabbit pAbs), ELISA kits, and ORF cDNA clones.

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    泛素-蛋白酶体途径 Background

    The ubiquitin-proteasome system (UPS) is responsible for the degradation of 70–90% of intracellular proteins. The fundamental importance of the ubiquitin-proteasome system in these degradation mechanisms was highlighted when Rose, Hershko, and Ciechanover were awarded the 2004 Nobel Prize in Chemistry for their seminal contributions in that field, i.e. the discovery of both ubiquitin and the proteasome. In recent years, proteolysis by the ubiquitin-proteasome pathway has attained prominence as a new molecular mechanism that regulates many vital functions of the nervous system, including development of synaptic connections and synaptic plasticity. The role of ubiquitin-proteasome pathway in neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease has also been highlighted.

    Ubiquitin is a small protein that is found only in eukaryotic organisms. The ubiquitin protein consists of 76 amino acids and has a molecular mass of about 8.5 kDa. The amino acid sequence of ubiquitin is highly conserved, and does not differ much when very different organisms are compared. This strong sequence conservation suggests that the vast majority of amino acids that make up ubiquitin are essential as apparently any mutations that have occurred over evolutionary history have been removed by natural selection.

    Ubiquitin functions to regulate protein turnover in a cell by closely regulating the degradation of specific proteins. It binds to proteins and labels them for destruction. The ubiquitin tag directs proteins to the proteasome, which is an organelle in the cell that degrades and recycles unneeded proteins. Proteasomes are part of a major mechanism by which cells regulate the concentration of particular proteins and degrade misfolded proteins. The degradation process yields peptides of about seven to eight amino acids long, which can then be further degraded into amino acids and used in synthesizing new proteins.

    In the ubiquitin-proteasome pathway, three critical enzymes are needed. E1 enzymes are known as ubiquitin-activating enzymes. They modify ubiquitin so that it is in a reactive state. E2 enzymes that are known as ubiquitin-conjugating enzymes catalyze the attachment of ubiquitin to the substrate protein. E3 enzymes are known as ubiquitin-ligases. E3 usually function in concert with E2 enzymes, but they are thought to play a role in recognizing the subtrate protein. The process of marking a protein with ubiquitin (ubiquitylation or ubiquitination) consists of a series of steps: First, ubiquitin is activated by E1 in an ATP-dependent fashion. E2 and E3 then work together to recognize the substrate protein and conjugate ubiquitin to it. Ubiquitin can be attached as a monomer or as a previously synthesized chain. From this point, the ubiquinated protein is shuttled to the proteasome for degradation.

    Deregulation of components of the ubiquitination machinery appears to be a common theme in the development of cancers. Mutations or overexpression of numerous E3 ubiquitin ligases can convert them to potent oncogenes and some E3s and DUBs act as tumor suppressors. Several substrates that are affected by alterations in E3 and DUB activity play key roles in the cell cycle, DNA repair, NF-κB signaling, RTK signaling and angiogenesis and their levels or activity are precisely regulated by ubiquitination.

    泛素-蛋白酶体途径 References

      1. Ciechanover A, et al. (1980) ATP-dependent conjugation of reticulocyte proteins with the polypeptide required for protein degradation.Proc Natl Acad Sci U S A. 77(3):1365–1368.
      2. Rose IA, et al. (1979) A high molecular weight protease in liver cytosol. J Biol Chem. 254(17):8135-8.
      3. Hegde AN, et al. (2007) The ubiquitin-proteasome pathway in health and disease of the nervous system. Trends Neurosci. 30(11):587-95.
      4. Depre C, et al. (2010) The role of the ubiquitin-proteasome pathway in cardiovascular disease. Cardiovasc Res. 85(2):251-2.
      5. Stangl K, et al. (2010) The ubiquitin-proteasome pathway and endothelial (dys)function. Cardiovasc Res. 85(2):281-90.