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ZOMES: "PROTEASOME, COP9 SIGNALOSOME AND TPPII"
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The proteasome
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The proteasome is the central enzyme of non-lysosomal protein degradation. It is responsible for intracellular protein turnover, involved in many regulatory processes and, in higher eukaryotes, responsible for antigen processing. The term “proteasome” refers to a number of multisubunit proteolytic entities, some of which are shown in schematic form below.
The 20S proteasome, which forms the catalytic core of the complex, is shown in two forms: a constitutive form (a) and an inducible form (b) containing the β1, β2, and β5 inducible subunits (shown in pink) responsible for generating inducible peptides for antigen presentation. At least six different forms of the mammalian 20S proteasome exist comprising varied subunit composition (B. Dahlmann et al. Biochimie 2001 83 295). The 19S regulatory complex (e), comprised of a lid (c) and base sub-complex (d), associates with either or both ends of the 20S complex. The 19S regulator is involved in the recognition, binding and de-ubiquitinylation of ubiquitinylated proteins tagged for destruction, unfolds and inserts the ubiquitinylated proteins into the core of the 20S proteasome, and stimulates its proteolytic activity.
The 11S activator (or PA28 complex) (f) is a further activator, which also can associate with one or both ends of the 20S proteasome alone or in combination with a 19S regulatory complex. The 11S activator modulates the proteasome-catalyzed production of antigenic peptides presented to the immune system on MHC class I molecules. That which is commonly referred to as the “26S proteasome” can be either a 30S complex (g) consisting of a 20S particle capped at both ends by 19S complexes or a 26S particle (h) capped only at one end. Two forms of the immunoproteasome may also be assembled. A chimeric form (i) consists of one inducible form of the 20S core, one 19S regulatory complex and one 11S activator complex and a second form (j) consists of the same 20S core capped at both ends by 11S activators. The 26S proteasome contains two copies each of 32- 34 subunits, 14 in the 20S core and 18-20 in the 19S regulator, with a total mass of ~2.5 MDa.
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COP9 signalosome
The COP9 signalosome (CSN) is a multisubunit protein complex associated with the ubiquitin proteasome pathway. The CSN complex is composed of eight subunits1, each of which is related to one of the eight subunits that form the lid of the 26S proteasome 19S regulatory particle2. The CSN was first identified in Arabidopsis where it is required for the repression of photomorphogenic seedling development in the dark3. CSN or CSN-related complexes have now been reported from most eukaryotic model organisms and the CSN has been implicated in a vast array of biological processes. It is now widely accepted that the CSN directly interacts with cullin containing E3 ubiquitin ligases, and that the CSN is required for their proper function4.
The requirement of the CSN for proper E3 function may at least in part be explained by the observation that the CSN subunit 5 (Csn5) is the isopeptidase that deconjugates the essential ubiquitin-like Nedd8 modification from the E3 cullin subunit5. In addition to its interaction with E3s, the CSN may also regulate proteolysis by its association with protein kinases and deubiquitylating enzymes. CSN subunits have been identifi ed as interactors of a diverse set of mammalian signaling proteins such as the transcription factor c-JUN and p53, the cell cycle regulator p27Kip1, hormone receptors, the macrophage migration inhibitory factor (MIF1), and the integrin LFA-1. These interactions may refl ect the multitude of processes that require CSN function6. It is not understood why these proteins interact directly with the CSN and at the same time with CSN-interacting E3 ubiquitin ligases. Notably, many of the interacting proteins have been reported to be targeted for degradation by the 26S proteasome7.
1. M. Seeger et al. FASEB J. 1998 12 469
2. M.H. Glickman et al. Cell 1998 94 615
3. N. Wei et al. Cell 1994 78 117
4. C. Schwechheimer et al. Plant Cell 2002 14 2553
5. G.A. Cope et al. Science 2002 298 608
6. C. Schwechheimer, Biochim. Biophys. Acta 2004 1695 45
7. O. Harari-Steinberg et al. Current Protein Pept. Sci. 2004 5 185 |
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TPPII
TPPII plays a critical role in cleaving proteasomal-produced peptides into tripeptides that can be further degraded by dipeptidyl peptidase II (DPPII) and aminopeptidases. There are also more specific roles for TPPII, such as its role in major histocompatibility complex (MHC) class I antigen processing. Native TPPII is a high molecular mass homomeric protein where the subunit (138 kDa) forms a large cylinder-like and well-organized complex (Mr>106)1, approximately 17 nm in diameter and 50 nm in length. The enzyme has a catalytic domain of the subtilisin-type, but in comparison with other subtilases, it has a 200 amino-acid insertion between the Asp and His of the catalytic triad 2,3
1. E. Macpherson et al. Biochem J. 1987 248 259
2. R.M. Balow et al. J Biol Chem. 1986 261 2409
3. R.J. Siezen and J.A. Leunissen Protein Sci. 1997 6 501 |
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