Open question: Which proteins are degraded by proteasome?
Why ATP--> AMP + PP ?
The proteasome is a multimeric protein-destroying apparatus which has been highly preserved along the philogenetic pathway.
It is involved in many fundamental biological processes: it is capable of degrading a variety of cellular proteins in a rapid and timely fashion and most substrate proteins are modified by ubiquitin before their degradation by the proteasome. It is part of the “proteostasis network” that together with the “unfolded proteins response” (UPR) and the “heat shock response” (HSR) regulate proteins and peptide half-life and turnover.
The proteasome is a large protein complex consisting of a proteolytic core called the 20S particle and ancillary factors that regulate its activity in various ways. The most common form is the 26S proteasome containing one 20S core particle and two 19S regulatory particles that enable the proteasome to degrade ubiquitinated proteins by an ATP-dependent mechanism(2000 KDa). Every proteasome is made up of one 20S nucleus formed by 4 heptamers of subunit assembled in a hollowed cylinder: some of this subunits are protease faced to the centre of the hollow, and recognize different substrates. At the extremities of this complex there are two 19S “Lid- shaped” formed by 20 subunits which work like gates and recognize the polyubiqutinated aminoacids.
The alternative form is the immunoproteasome containing two 11S regulatory particles (ends positions instead of 19S), PA28 alpha and PA28 beta, which are induced by interferon gamma under the conditions of intensified immune response. Other regulatory particles include PA28 gamma and PA200. Although PA28 gamma also belongs to a family of activators of the 20S proteasome, it is localized within the nucleus and forms a homoheptamer. PA28 gamma has been implicated in the regulation of cell cycle progression and apoptosis. PA200 has been identified as a large nuclear protein that stimulates proteasomal hydrolysis of peptides.
The proteasome is located both in the nucleus and in the cytoplasm in elevated number (also many ER proteins can be proteasome’s targets).
From the distribution of the alfa subunit PSA6 is possible to realize that tissues with very high turnover have higher expression.
The process of unfolding of the protein that will be degraded is pivotal, if this process is hampered by particular sequences like Ala or Gly the process of degradation could be blocked: some viruses like EBV are able to exploit this phenomenon.
Moderately oxidised proteins can stimulate the protesome but highly oxidized ones inhibit the protesome.
IFN and TNFalfa not only regulates proteasome but even modulate the trascription of different subunits to better respond to the environment requests.
Interferon-γ inducible exchanges of 20S proteasome active site subunits: Why?
Many proteasome inhibitors have been identified and can be classified into two groups according to their source: chemically synthesized small molecules and compounds derived from natural products. A successful example of development of a proteasome inhibitor as a clinically useful drug is the peptide boronate, PS341 (Bortezomib), was approved for the treatment of multiple myeloma . In contrast to proteasome inhibitors, small molecules that can activate or enhance proteasome activity are rare and are not well studied. The fact that overexpression of the cellular proteasome activator PA28 exhibited beneficial effects on the Huntington's disease neuronal model cells raised the prospect that small molecule proteasome activators could become useful therapeutics. The beneficial effect of oleuropein, a small molecule proteasome activator, on senescence of human fibroblasts also suggested that proteasome activators might have the potential to be developed into anti-aging agents.
In a recent analysis, was identified a frequent humoral autoimmune response directed against specific proteasomal subunits in patients with autoimmune myositis, systemic lupus erythematosus and primary Sjögren's syndrome.