Proteasome

The proteasome (also: Macro Pain) is a protein of 1,700 kDa complex which degrades proteins into fragments in the cytoplasm and in the nucleus (for eukaryotic cells ) and, therefore, the peptidases (including proteases ) is one. The proteasome is a component of the protein quality control.

Structure

The 26S proteasome consists of a 20S in eukaryotes, 19S and two subunits, which in turn are re-assembled from a plurality of proteins. The proteasomes from prokaryotes lack the 19S subunits. The size of the proteasome is 17 nm × 11 nm

20S subunit

The 20S subunit is in the form of a hollow cylinder and acts as a multi- catalytic protease. It consists of four rings, which in turn are assembled from seven subunits ( α1 to α7, and β1 to β7 ). The two inner rings are made of β - subunits, the outer two of α - subunits. The outer rings are responsible for substrate recognition and substrate access. It can reach only unfolded proteins in the proteasome, as the diameter of the tertiary structures to be small. On the inner wall of the β -ring, the proteolytic activity is located The subunits β1, β2 and β5 exhibit protease activity, the other not. Each of these subunits has a slightly different proteolytic Aktivtität: β1 cleaves the peptide chain of the unfolded protein of acidic amino acids ( caspase -like activity ), β2 cleaves after basic amino acids ( trypsin-like Aktivtität ) and β5 cleaves after hydrophobic amino acids ( chymotrypsin-like Aktivtität ).

19S subunit

The 19S complexes sit in eukaryotes as a lid (cap ) on the two openings of the 20S complex. They regulate access to the 20S complex and recognize and develop to reduce certain proteins. The 19S subunit is composed of Rpn and Rpt proteins. Rpn recognizes the marked for degradation proteins on the basis of ubiquitin molecules and binds them. Rpt contrast hydrolyzed adenosine triphosphate (ATP ) so that necessary energy is obtained. (only unfolded proteins fit into the 20S complex into it ).

Target proteins

Proteins to be degraded are marked in a multistep enzymatic process with a polyubiquitin chain that is recognized by the 19S complexes. Ubiquitin is a small protein with a molecular mass of 8.5 kDa. The polyubiquitin chain is decomposed by reduction to their individual ubiquitin molecules which can then be reused. Protein degradation is essential for the cell. As metabolic enzymes, transcription factors, or cell cycle regulatory proteins such as cyclins, CDK inhibitors are degraded. Similarly, defective proteins are degraded. The peptides bound to the major histocompatibility complex I on the surface of the cell to the immune system, are processed in the proteasome (see also section immunoproteasome ).

Importance

These features make the proteasome to a central switch within the cell. As the latter and in particular also because of its function in the cell cycle, the proteasome is considered to be a potential target for therapy of various diseases, including cancer. Proteasome inhibitors, that is, chemical substances that inhibit the activity of the proteasome, are currently in clinical investigation as drugs against certain tumors and neurodegenerative diseases such as Huntington's disease. The first approved proteasome inhibitor, bortezomib, is effective against multiple myeloma, a malignant plasma cell disorder.

Immunoproteasome

The catalytic subunits β1, β2 and β5 are also referred to as constitutive subunits and the complete 20S proteasome with these subunits as a constitutive proteasome. This detailed specification is important for the special role of the proteasome in the context of an immune response. In the course of such cells are exposed at locations penetrating pathogens (viruses, bacteria, parasites) by cells of the immune system to the cytokine interferon- γ. Characterized the cells alter the expression of different genes, whereby the immune response is supported. Instead of the three proteasome subunits β1, β2 and β5 then the subunits low molecular mass protein 7 ( LMP7, also β5i ) Multicatalytic endopeptidase complex -like 1 ( MECL -1, also β2i ) and LMP2 (also β1i ) in the 20S core Particle installed. The thus composed proteasome is therefore referred to as the " immunoproteasome ." The immunoproteasome has numerous functions in the immune response, such as a stronger presentation of antigens on MHC class I compared to the constitutive proteasome. In cells of the immune system (eg lymphocytes) is permanently formed the immunoproteasome.

Thymoproteasom

In addition to the proteasome and the immunoproteasome konstituvien there is a third class of the proteasome, which is found exclusively in the cortical epithelial cells of the thymus. Here, the sub-unit is replaced by the alternative β5 subunit β5t ( "t" for thymoproteasome ). Cortical epithelial cells of the thymus plays an important role in the process of positive selection during the development of T lymphocytes. The exact function of Thymoproteasoms in this process is not known yet.