Proteasomes are multiunit protein complexes involved in protein degradation. The mechanism is of importance since they play a key role in selectively degrading non functional and damaged proteins. The complex is preent in nucleus as well as cytosol of all eukryotic cells. A typical human cell contains about 30000 proteasome complexes each weighing about 700 kDa.
The 26 S proteasome complex is made of 3 major subunits.
1. a 20 S core complex and
2. Two 19S subunits (regulatory particles)
20S core complex is composed of two units each of 14 different polypeptide chains. The polypeptides are arranged in groups of 7 with 7 alpha and 7 beta proteins. They form four ring-like structures stacked one above the other forming a cylinder. The alpha units form the outer rings and the beta rings form the interior. There is a narrow cavity
The 19S subunits are identical in nature and form the ends of the 20S cylindrical core complex. Each subunit in turn is composed of 18 different polypeptides which are different from that of core particle. Six of the chains are ATPases which help in ATP hydrolysis. The subunits also have ubiquitin-recognizing sites.
Proteasomes are involved in degradation of endogenous proteins such as transcription factors, cyclins, proteins damaged by translation errors, viral and other pathogenic proteins etc.
Three beta subunits act as proteases on different substrates.
a. Act on tyrosine or Phenylalanine residues at C' end. Similar to Chymotrypsin in activity.
b. Act on arginine or lysine at P1 end like trypsin.
c. The third one prefers glutamate or any acidic aminoacids at the P1 position.
Major cell processes such as cell division, apoptosis, differentiation and development involve proteasomal degradation. Proteasome mediated degradation of cyclins control the progress of cell cycle through different stages. Cyclins are responsible for activation of cyclin dependent kinases. Similarly, proteasomal subunits are inactivated by glycosylation when the extracellular levels of glucose are high thus controlling the proteolysis inside the cell.
The 19S regulatory subunits recognize the proteins which are polyubiquitinated, remove ubiquitin and unfold proteins for degradation. The ubiquitin-mediated protein degradation is involved in many important processes such as intracellular signal transduction, regulation of gene expression, embryonic development, apoptosis, and control of cell division. Ubquitination is also a marking strategy for proteins which are misfolded or mistranslated for degradation. The 19S subunits are thus involved in multitasking and therefore are energy-dependent (ATP-requiring) for their functioning.
The 2004 Noble Prize in Chemistry was shared by Ciechanover, Hershko and Rose for the discovery of ubiquitin mediated protein degradation. With that further research in protein degradation has grown rapidly and had unearthed further roles of proteasomes.
The 19S subunit has been studies in detail and found to have multicatalytic nature. They serve as checking point to allow the proteins into the 20S complex selectively for degradation.
They are found in higher vertebrates and are involved with immune system. In these proteasomes, the regular catalytic subunits are replaced by three homologous beta subunits. They also produce peptides which can alter the response of TCD8+ cells to viral proteins. They are constitutively expressed in the tissues involved in immune function. Gamma interferons(IFN) and Tumor Necrosis factor (TNF-alpha) and cytokines are known to induce the production of immunoproteasomes in other cells. They are found in association with TAP (Transporter associated with Antigen Presentation).
The viral proteins are labeled with MHC-I molecules. They fuse with the cell membrance which results in activation of cytotoxic T cells to initiate the immune response.
Difference from standard proteasomes
a.) They also differ from standard proteasomes in the speed of maturation process. Generally, proteasomes don't get activated until the 20S structure is assembled. The catalytic subunits are kept inactive till the amino terminal propeptide is removed and an active threonine residue is added. The immunoproteasomes are found to be four times faster than standard ones in maturation.
b.) Immunoproteasomes are relatively less stable when compared to standard proteasomes. However, in case of viral infections in presence of increased cytokine release has been found to accelerate the degradation of standard proteasomes so that immunoproteasomes are abundant.
The immunoproteasomes as such deserve further researches to explore the role in normal cells, regulation and the role in other tissues with little or no immunogenic function.
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