The Proteasome

One of the most fascinating recent developments in biology has been the discovery of numerous highly complex biopolymer assemblies (see also section C2.14.2.3) such as the ribosome or the bacterial flagellum [93, 94 and 95], the envy of nanoteclmologists seeking to miniaturize man-made mechanical devices (note that the word machinery is also sometimes used to refer to multienzyme complexes such as the proteasome [96]), and an entire... 

Baumeister W, Walz J, Zuhl F and Seemuller E 1998 The proteasome paradigm of a self-oompartmentalizing protease Cell 92 367-80... 

Antineoplastic agents that cannot be grouped under subheadings 1-9 include miltefosine which is an alkylphosphocholine that is used to treat skin metastasis of breast cancer, and crispantase which breaks down asparagine to aspartic acid and ammonia. It is active against tumor cells that lack the enzyme asparaginase, such as acute lymphoblastic leukemia cells. Side effects include irritation of the skin in the case of miltefosine and anaphylactic reactions in the case of crispantase. Another recent development is the proteasome inhibitor bortezomib which is used to treat multiple myeloma. 

The human genome contains more than 90 different DUBs. Besides cleaving ubiquitin from distinct substrates, DUBs are also responsible for the recycling of free ubiquitin from ubiquitin chains and processing of ubiquitin- or ubiquitin like precursor proteins. Certain DUBs are also associated with the proteasome in order to detach ubiquitin chains before proteolysis. 

ER-Associated Degradation, when proteins mis-fold in the ER due to mutation or environmental conditions, they are selectively exported to the cytosol for degradation by the proteasome. 

Threonine peptidases (and some cysteine and serine peptidases) have only one active site residue, which is the N-terminus of the mature protein. Such a peptidase is known as an N-terminal nucleophile hydrolase or Ntn-hydrolase. The amino group of the N-terminal residue performs the role of the general base. The catalytic subunits of the proteasome are examples of Ntn-hydrolases. 

An enzyme in which the single catalytic residue is at the N-terminus of the protein. Many Ntn-hydrolases are synthesized as precursors and autoactivate the precursors are therefore peptidases, even if the mature enzyme has no further proteolytic activity. Three of the beta subunits of the proteasome are Ntn-hydrolases. 

Protein modification by the covalent attachment of ubiquitin chains serves as a signal to mark proteins for the degradation by a multicatalytic proteinase complex called the proteasome. Thus the ubiquitin proteasome system (UPS) controls the stability of proteins in a... 

Ubiquitin is a highly conserved 8.5 kDa polypeptide, which was first described in 1974. The discovery that the Ubiquitin proteasome system serves as a general mechanism to target proteins for destruction by the proteasome was awarded with the Nobel Prize for Chemistry in 2004. 

The UPS also plays a major role in protein quality control. In a process known as endoplasmic associated degradation (ERAD), misfolded proteins, which are formed in the endoplasmatic reticulum, are translocated back to the cytoplasm and degraded by the proteasome. 

Several aryl esters of 6-chloromethyl-2-oxo-2//-l -benzopyran-3-carboxylic acid act as human Lon protease inhibitors (alternate substrate inhibitors)46 without having any effect on the 20S proteasome. Proteasomes are the major agents of protein turnover and the breakdown of oxidized proteins in the cytosol and nucleus of eukaryotic cells,47 whereas Lon protease seems to play a major role in the elimination of oxidatively modified proteins in the mitochondrial matrix. The coumarin derivatives are potentially useful tools for investigating the various biological roles of Lon protease without interfering with the proteasome inhibition. 

ASBA has been used to identify parasite adhesive proteins (Gowda et al., 2007), for active site-directed labeling of glucosidase I (Romaniouk et al., 2004), and to study interactions with the proteasome (Qureshi et al., 2003). 

Minami, Y. et al. (2000a) A critical role for the proteasome activator PA28 in the Hsp90-dependent protein refolding./. Biol. Chem. 275(12), 9055-9061. 

Qureshi, N., Perera, P.-Y., Shen, J., Zhang, G., Lenschat, A., Splitter G., Morrison, D.C., and Vogel, S.N. (2003) The proteasome as a lipopolysaccharide-binding protein in macrophages Differential effects of proteasome inhibition on lipopolysaccharide-induced signaling events. J. Immunol. 171, 1515. 

The proteasome is a cytoplasmic protein degradation machine that hydrolyses proteins, which have been designated for degradation by having a number of molecules of the small ubiquitous protein, ubiquitin, attached to them. 

COULOMBE, P., Rodiee, G., Bonneil, E., Thibault, P. and Meloghe, S. N-Terminal ubiquitination of extracellular signal-regulated kinase 3 and p21 directs their degradation by the proteasome. Mol. Cell Biol, 2004, 24, 6140-6150. 

---