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Friday, November 18, 2011

Ubiquitin: The Ubiquitous Protein and its Importance

Ubiquitin is a small regulatory protein found in the tissues of eukaryotic organisms. Ubiquitin contists of 76 amino acids and has a molecular weight of 8.5KDa. Among the 76 amino acids 7 are lysine residues. ubiquitin also has features of heat shock proteins (HSP).
Ubiquitin is a heat-stable protein that folds up into a compact globular structure. It is found throughout the cell and can exist either in free form or as part of a complex with other proteins. In the latter case, Ubiquitin is attached (conjugated) to proteins through a covalent bond between the glycine at the C-terminal end of Ubiquitin and the side chains of lysine on the proteins. Single Ubiquitin molecules can be conjugated to the lysine of these proteins, or more commonly, Ubiquitin chains can be attached. Conjugation is a process that depends on the hydrolysis of ATP.
Ubiquitin can be attached to proteins and label them for destruction. The ubiquitin tag directs proteins to the proteasome, which is a large protein complex in the cell that degrades and recycles unneeded proteins.Ubiquitin tags can also direct proteins to other locations in the cell, where they control other protein and cell mechanisms.


Ubiquitination is a post-translational modification carried out by a set of three enzymes, E1, E2 and E3. Ubiquitin is first activated by ubiquitin-activating enzyme E1, before being transferred to its active site, the amino acid cystein. This transfer requires ATP, making the process energy-dependent. The ubiquitin molecule is then passed on to the second enzyme of the complex, E2 (ubiquitin-conjugating enzyme), before reaching the final enzyme, E3, the ubiquitin protein ligase, which recognises, binds the target substrate and labels it with the ubiquitin. The process can be repeated until a short chain is formed, with three or more ubiquitin molecules usually targeting the protein to the proteasome
The tricky part of this whole process is making sure that ubiquitin is attached only to the proper proteins. Several specialized enzymes sort through the proteins in the cell and pick only the right ones. The E1 enzyme is the ubiquitin-activating enzyme that starts the process. Powered by ATP, it attaches the tail end of ubiquitin to one of its own cysteine amino acids. Then, E1 passes the activated ubiquitin to one of several E2 enzymes, the ubiquitin-conjugating enzymes, These E2 enzymes then work with a large number of different E3 enzymes to recognize obsolete proteins and attach the ubiquitin to them. The E3 enzyme is shaped like a big clamp. The target protein binds in the gap The left side of the enzyme recognizes the protein and the right side positions E2 to allow transfer of its ubiquitin.
Once an unwanted (not needed in the cell) proteins are tagged with at least four ubiquitin molecules, they are destroyed by proteasomes. Proteasomes are voracious protein shredders, but the destructive machinery is carefully protected so that it can't attack all of the normal proteins in the cell. The proteasome, is shaped like a cylinder, with its active sites sheltered inside the tube. The caps on the ends regulate entry into the destructive chamber, where the protein is chopped into pieces 3 to 23 amino acids long.
Ubiquitination and Disease Development
In certain cancers, oncogenic targets (such as the adenovirus E1 A or the oncogene c-myc) are mutated so that they are no longer subject to ubiquitination, and therefore escape degradation and accumulate in the cell. The human papilloma virus (HPV), responsible for certain forms of cervical cancer, relies on its own viral E6 protein to promote ubiquitin-mediated degradation of the tumour suppressor p53. Other cancers may promote the over-expression of E3 ligases such as mdm2 leading enhanced degradation of p53.
Ubiquitination also plays a part in diseases involving membrane proteins, such as Cystic Fibrosis, where ubiquitination is responsible for the degradation of the mis-folded CFTR chloride ion channel, or Liddle's syndrome, where a mutation in a E3 ligase (NEDD4) prevents the efficient ubiquitin-mediated degradation of the ENaC epithelial sodium channel, leading to hypertension through excessive sodium and water re-absorption.
(From Ubiquitination: labelling the proteins SEB Bulletin 2008)

Ubiquitin System Functions
The ubiquitination system functions in a wide variety of cellular processes, including:
  • Antigen processing
  • Apoptosis
  • Biogenesis of organelles
  • Cell cycle and division
  • DNA transcription and repair
  • Differentiation and development
  • Immune response and inflammation
  • Neural and muscular degeneration
  • Morphogenesis of neural networks
  • Modulation of cell surface receptors, ion channels and the secretory pathway
  • Response to stress and extracellular modulators
  • Ribosome biogenesis
  • Viral infection
The studies on ubiquitination goes beyond cancer and neurodegenerative diseases.With the rapid improvements in technologies and drug development, the relevance of these studies is tremendous. As a result, one successful anti-cancer drug has been developed and is already in use (Bortezomib, it is the first therapeutic proteasome inhibitor marketed as Velcade by Millenium Pharmaceutical), while many others are in the pipeline. Future research will be focused on specific recognition of novel target proteins by the system, with the hope to develop specific modulators that will be able to control the level of key regulatory proteins involved in basic cellular processes in health and disease.

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