Proteasome

Aaron Ciechanover, Avram Hershko and Irwin Rose were awarded the Nobel Prize in Chemistry in 2004 for the discovery of ubiquitin-directed protein degradation.

A proteasome is a cylindrically structured protein complex that "shreds" unfolded proteins by means of adenosine triphosphate-dependent proteolysis. The cell enzymes combined in the proteasome are significantly involved in protein degradation outside the lysosomes in humans (see also ubiquitination). The proteasome plays an essential role in antigen processing (see MHC below).

The proteasome is a 1,700 kDa protein complex that is found in the cytoplasm and also in the nucleus of eukaryotes. As a component of protein quality control, the proteasome degrades proteins into fragments. The enzyme complex belongs to the proteases (peptidases).

The proteasome in eukaryotes consists of one 20S and two 19S subunits, which in turn are composed of several proteins. In eukaryotes, the 19S complexes sit cap-like on the two openings of the 20S complex, a tube-like hollow structure.

Both caps regulate access to the 20S complex. They recognize proteins destined for degradation, label them with a polyubiquitin chain in a multi-step enzymatic process using ubiquitin-protein ligases. The proteins labeled and unfolded in this way now fit into the 20S complex. They are enzymatically disassembled there. Ubiquitin is a small protein with a molecular mass of 8.5 kDa.

Protein degradation is vital for the cell. Thus, metabolic enzymes, transcription factors or proteins regulating the cell cycle such as cyclins, CDK inhibitors are degraded. Likewise, defective proteins are degraded.

Peptides bound to major histocompatibility complex I on the surface of the cell presented to the immune system are also processed in the proteasome. The "loading" of the MHC-I molecule is controlled by a membrane-bound macromolecular machinery called the peptide loading complex - PLC ( = peptide loading complex). The MHC-I peptide complex is eventually transported to the cell surface for presentation of the peptides to the immune system (via the TCR of CD8-positive lymphocytes) for induction of antibodies.

Immunoproteasome: This is a "specialized proteasome". This has altered catalytic beta subunits and is expressed in an immunological response by some hematopoietic cells. The following subunits are altered:

• Beta1i: LMP2 (low molecular mass protein 2).
• Beta2i: MECL-1 (multicatalytic endopeptidase complex like 1)
• Beta5i: LMP7 (low molecular mass protein 7) - see below. PSMB8 gene (chromosome 6p21.32) encoding this subunit.

A proteasome assembled in this way is called an immunoproteasome. The immunoproteasome is able to express antigens in an enhanced manner compared to a normal ("constitutive") proteasome. In some immune cells (e.g. lymphocytes) the immunoproteasome is permanently formed.

Inhibition of this natural protein degradation leads to an accumulation of degradable proteins, just like on a garbage dump. Due to the lack of disposal of cell-internal proteins, cell cycle and DNA repair mechanisms are inhibited and apoptosis is enhanced. Since protein synthesis and degradation are activated in tumor cells, they react more sensitively to inhibition of their proteasome activity than non-malignant cells (see also proteasome inhibitors).

1. Becker JC et al (2006). New therapeutic approaches for solid tumors: histone deacetylase, methyltransferase and proteasome inhibitors. J Dtsch Dermatol Ges 4: 108-113