Proteasome Activators

As the ubiquitin proteasome pathway is a main route for protein clearance it is not surprising that in protein-opathies (disease caused by aggregate prone proteins) like sporadic Parkinson- or Huntington disease proteasome activity is reduced. Autosomal recessive loss of function of the E3 ligase parkin is the molecular base for one of the most common forms of familial Parkinson disease. 

In the NF-kB pathway with celastrol 76, the inhibition of the iKBa degradation is due to the upstream blockage of the kinase activity and not by the direct inhibition of proteasome activity. On the contrary, direct inhibition of proteasome activity was observed with celastrol 76 and pristimerin 2 in prostate cancer cells.90-92 Both triterpene QMs directly inhibited the activity of the 20S subunits of proteasome at 2.5 iM and induced the accumulation of ubiquitinated proteins over time in cells,... 

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. 

Longva, K. E., et al., Ubiquitination and proteasomal activity is required for transport of the EGF receptor to inner membranes of multivesicular bodies. J Cell Biol, 2002, 156(5), 843-54. 

Eukaryotic genomes contain information for more than 20 E2s and hundreds of E3s. In contrast to the wealth of components devoted to marking protein substrates for destruction, only one enzyme, the 26S proteasome, has been found to degrade ubiquitylated proteins. However, there is complexity here as well, since the 26S proteasome is an assemblage of at least 30 different subunits. Moreover, there is a growing list of proteins that act as proteasome activators, adapters, or accessory factors. In this chapter I focus on basic biochemical and physiological properties... 

In addition to the RC there are two protein complexes, REGajS and REGy, and a single polypeptide chain, PA200, that bind the 20S proteasome and stimulate peptide hydrolysis but not protein degradation. Like the RG, proteasome activators bind the ends of the 20 S proteasome and, importantly, they can form mixed or hybrid 26S proteasomes in which one end of the 20S proteasome is associated with a 19S RC and the other is bound to a proteasome activator [147-150]. This latter property raises the possibility that proteasome activators serve to localize the 26S proteasome within eukaryotic cells. 

A new proteasome activator called PA200 was recently purified from bovine testis [156]. Human PA200 is a nuclear protein of 1843 amino acids that activates all three catalytic subunits with some preference for the PGPH active site. Homologs... 

Fenteany, G. et al. Inhibition of proteasome activities and subunit-specific amino-terminal threonine modification by lactacystin. Science 1995, 268, 726-731. 

Meinees, S. et al. Inhibition of proteasome activity induces concerted expression of proteasome genes and de novo formation of Mammalian proteasomes. J Biol Chem 2003, 278, 21517-25. 

Murata, S. et al. Growth retardation in mice lacking the proteasome activator PA28gamma. J Biol Chem 1999, 274, 38211-5. 

Ustrell, V., Hoffman, L., Pratt, G., and Rechsteinee, M. PA200, a nuclear proteasome activator involved in DNA repair. EMBO J. 2002, 21, 3403-3412. 

Gao, Y., Post, M. J., and Simons, M. Proline- and arginine-rich peptides constitute a novel class of allosteric inhibitors of proteasome activity. Biochemistry 2003, 42, 8663-70. 

Fenteany, G., Standaert, R. F., Lane, W. S., Choi, S., Corey, E. J., and Schreiber, S. L. Inhibition of proteasome activities and subunit-spedfic amino-terminal threonine modification by lactacystin. Science 1995, 268, 726-731. 

P., and Goldberg, A. L. An archaebacterial ATPase, homologous to ATPases in the eukaryotic 26 S proteasome, activates protein breakdown by 20 S proteasomes. J. Biol. Chem. 1999, 274, 26008-26014. 

Fig. n.3. Non-canonical functions of PA700 in the regulation of proteasome activity. A)... 

Proteasome activity can be regulated in two main ways. One is regulation by cofactors or proteins that are loosely associated with it and by induction or phosphorylation of the subunits especially those of the 19S RC. The proteasome can also be regulated by a change in the composition of the intrinsic subunits (Figure 6(c)). 

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