Download Student CSE paper

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 deubiquitinating 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.
Ubiquitin/Proteasome Pathway 12
References
1. De Silva HR, Khan NL, Wood NW. The genetics of Parkinson’s disease. Curr
Opin Genet Dev. 2000;10(3):292-298.
2. Figueiredo-Pereira ME, Rockwell P. The ubiquitin/proteasome pathway in
neurological disorders. In: Banik NL, Lajtha A, editors. Role of proteases in the
pathophysiology of neurodegenerative diseases. New York: Kluwer/Plenum;
2001. 302p.
3. 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.
4. 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
5. 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.
6. 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. 1999;145(3):481-490.