Proteasome activators. Mol Cell

Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT 84112-5650, USA.
Molecular cell (Impact Factor: 14.02). 01/2011; 41(1):8-19. DOI: 10.1016/j.molcel.2010.12.020
Source: PubMed


Proteasomes degrade a multitude of protein substrates in the cytosol and nucleus, and thereby are essential for many aspects of cellular function. Because the proteolytic sites are sequestered in a closed barrel-shaped structure, activators are required to facilitate substrate access. Structural and biochemical studies of two activator families, 11S and Blm10, have provided insights to proteasome activation mechanisms, although the biological functions of these factors remain obscure. Recent advances have improved our understanding of the third activator family, including the 19S activator, which targets polyubiquitylated proteins for degradation. Here we present a structural perspective on how proteasomes are activated and how substrates are delivered to the proteolytic sites.

Download full-text


Available from: Beth Stadtmueller, Nov 04, 2014
  • Source
    • "However, endogenous inhibitors like Hsp 90, P131, PR 39, and Tat have also been described. The biological role of 26S proteasomes and its activators and inhibitors have been reviewed extensively elsewhere [5] [7] [24] [25]. New regulatory mechanisms have emerged. "
    [Show abstract] [Hide abstract]
    ABSTRACT: In eukaryotic cells, proteasomes perform crucial roles in many cellular pathways by degrading proteins to enforce quality control and regulate many cellular processes such as cell cycle progression, signal transduction, cell death, immune responses, metabolism, protein-quality control, and development. The catalytic heart of these complexes, the 20S proteasome, is highly conserved in bacteria, yeast, and humans. However, until a few years ago, the role of proteasomes in parasite biology was completely unknown. Here, we summarize findings about the role of proteasomes in protozoan parasites biology and virulence. Several reports have confirmed the role of proteasomes in parasite biological processes such as cell differentiation, cell cycle, proliferation, and encystation. Proliferation and cell differentiation are key steps in host colonization. Considering the importance of proteasomes in both processes in many different parasites such as Trypanosoma, Leishmania, Toxoplasma, and Entamoeba, parasite proteasomes might serve as virulence factors. Several pieces of evidence strongly suggest that the ubiquitin-proteasome pathway is also a viable parasitic therapeutic target. Research in recent years has shown that the proteasome is a valid drug target for sleeping sickness and malaria. Then, proteasomes are a key organelle in parasite biology and virulence and appear to be an attractive new chemotherapeutic target.
    Full-text · Article · Oct 2014 · BioMed Research International
  • Source
    • "The subunits of 20S proteasomes cluster to related a and b superfamilies (Coux et al. 1994) and respectively form two outer and two inner heptameric rings that create a barrelshaped complex (Löwe et al. 1995). Access to the inner chamber of 20S proteasomes, which house the catalytically active Thr residues, is through two small pore openings further restricted by axial gates (Stadtmueller and Hill 2011). Two conditions must be met for substrate translocation to the proteolytic active sites to occur: the protein must be unfolded and the 20S CP gate must be opened. "
    [Show abstract] [Hide abstract]
    ABSTRACT: In eukaryotes, the 26S proteasome degrades ubiquitinylated proteins in an ATP-dependent manner. Archaea mediate a form of post-translational modification of proteins termed sampylation that resembles ubiquitinylation. Sampylation was identified in Haloferax volcanii, a moderate halophilic archaeon that synthesizes homologs of 26S proteasome subunits including 20S core particles and regulatory particle triple-A ATPases (Rpt)-like proteasome-associated nucleotidases (PAN-A/1 and PAN-B/2). To determine whether sampylated proteins associate with the Rpt subunit homologs, PAN-A/1 was purified to homogeneity from Hfx. volcanii and analyzed for its subunit stoichiometry, nucleotide-hydrolyzing activity and binding to sampylated protein targets. PAN-A/1 was found to be associated as a dodecamer (630 kDa) with a configuration in TEM suggesting a complex of two stacked hexameric rings. PAN-A/1 had high affinity for ATP (K m of ~0.44 mM) and hydrolyzed this nucleotide with a specific activity of 0.33 ± 0.1 μmol Pi/h per mg protein and maximum at 42 °C. PAN-A1 was stabilized by 2 M salt with a decrease in activity at lower concentrations of salt that correlated with dissociation of the dodecamer into trimers to monomers. Binding of PAN-A/1 to a sampylated protein was demonstrated by modification of a far Western blotting technique (derived from the standard Western blot method to detect protein–protein interaction in vitro) for halophilic proteins. Overall, our results support a model in which sampylated proteins associate with the PAN-A/1 AAA+ ATPase in proteasome-mediated proteolysis and/or protein remodeling and provide a method for assay of halophilic protein–protein interactions.
    Full-text · Article · Dec 2013 · Extremophiles
  • Source
    • "In the closed 20SPT conformation, the N-termini of the Į-subunits form an intricate lattice of interactions that block access to the catalytic chamber through the so called Į-annulus, located just below the surface of the Į-heptameric ring. This conformation supposedly maintains a fixed opening of 13 -20 Å allowing the entrance of only small peptides [39]. The N-terminal of the Į3 subunit of yeast proteasome was shown to be essential for the closed conformation as it causes the stabilization of the neighboring tails of the Į-ring. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The proteasome is a multimeric and multicatalytic intracellular protease responsible for the degradation of proteins involved in cell cycle control, various signaling processes, antigen presentation, and control of protein synthesis. The central catalytic complex of the proteasome is called the 20 S core particle. The majority of these are flanked on one or both sides by regulatory units. Most common among these units is the 19 S regulatory unit. When coupled to the 19 S unit, the complex is termed the asymmetric or symmetric 26 S proteasome depending on whether one or both sides are coupled to the 19 S unit, respectively. The 26 S proteasome recognizes poly-ubiquitinylated substrates targeted for proteolysis. Targeted proteins interact with the 19 S unit where they are deubiquitinylated, unfolded, and translocated to the 20 S catalytic chamber for degradation. The 26 S proteasome is responsible for the degradation of major proteins involved in the regulation of the cellular cycle, antigen presentation and control of protein synthesis. Alternatively, the proteasome is also active when dissociated from regulatory units. This free pool of 20 S proteasome is described in yeast to mammalian cells. The free 20 S proteasome degrades proteins by a process independent of poly-ubiquitinylation and ATP consumption. Oxidatively modified proteins and other substrates are degraded in this manner. The 20 S proteasome comprises two central heptamers (β-rings) where the catalytic sites are located and two external heptamers (α-rings) that are responsible for proteasomal gating. Because the 20 S proteasome lacks regulatory units, it is unclear what mechanisms regulate the gating of α-rings between open and closed forms. In the present review, we discuss 20 S proteasomal gating modulation through a redox mechanism, namely, S-glutathionylation of cysteine residues located in the α-rings, and the consequence of this post-translational modification on 20 S proteasomal function.
    Full-text · Article · Dec 2013
Show more