Jennifer Martinez wrote a paper on neurological disorders for a biology class. This paper
is excerpted below, with references on the following page.
Proteolysis is the breakdown or degradation of proteins and is an important cellular event
involving tightly regulated removal of unwanted proteins and retention of those that are
essential. The ubiquitin/proteasome pathway plays an important role in the intracellular
quality control process by degrading mutated or abnormally folded proteins to prevent their
accumulation as intracellular aggregates. Proteolysis by the ubiquitin/proteasome pathway
involves two major steps: ubiquitination followed by degradation. A de-ubiquitination step
also plays an important role in this pathway 2 .
Ubiquitin (Ub) is a small peptide, consisting of 76 amino acids and is abundant in all
eukaryotic cells 2. Covalent attachment of ubiquitin to proteins targets them for degradation.
Once ubiquitinated, proteins do not accumulate in cells since the Ub/proteasome pathway
degrades them. Proteins become ubiquitinated by a series of four enzymatic reactions: the
ATP dependent activation of ubiquitin by Ub-activating enzymes (E1), binding of activated
ubiquitin to Ub-conjugating enzymes (E2), the covalent conjugation of ubiquitin to the
protein substrate by Ub-ligases (E3) and the formation of a polyubiquitin chain by the
elongation factor E4. Polyubiquitination acts as a tag for recognition by the 26S proteasome
for protein degradation. The 26S proteasome consists of two main particles, the 19S
regulatory particle and the 20S catalytic particle. The 19S particle has a lid and base
arrangement. The lid contains ATPases and de-ubiquitinating enzymes, whereas, the base
contains polyub-binding subunits. The 20S particle is a cylinder-shaped complex with a
catalytic core. The hydrolysis of peptide bonds occurs in this core particle 2,6.
References
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Figueiredo-Pereira ME, Rockwell P. The ubiquitin/proteasome pathway in
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pathophysiology of neurodegenerative diseases. New York: Kluwer/Plenum; 2001.
302p.
Imai Y, Soda M, Takahashi R. Parkin suppresses unfolded protein stress-induced cell
death through its E3 ubiquitin-protein ligase activity. J Biol Chem.
2000;275(46):35661-35664.
Parkinson’s disease—hope through research [Internet]. Bethesda (MD): Nat Inst of
Neurological Disorders and Stroke; updated 2006 Jun 27 [cited 2006 Jul 6]; [about
20p.]. Available from: http://www.ninds.nih.gov/disorders/ parkinsons_disease/
detail_parkinsons_disease.htm
Shimura H, Hattori N, Kubo S, Mizuno Y, Asakawa S, Minoshima S, Shimizu N,
Iwai K, Chiba T, Tanaka K, Suzuki T. Familial Parkinson disease gene product,
parkin, is a ubiquitin-protein ligase. Nat Genet. 2000;25(3):302-305.
Wigley WC, Fabunmi RP, Lee MG, Marino CR, Muallem S, Demartino GN, Thomas
PJ. Dynamic association of proteasomal machinery with the centrosome. J Cell Biol.
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