The proteasome is a multisubunit enzyme complex that plays a central role in the regulation of proteins that control cell-cycle progression and apoptosis, and has therefore become an important target for anticancer therapy. Before a protein is degraded, it is first flagged for destruction by the ubiquitin conjugation system, which ultimately results in the attachment of a polyubiquitin chain on the target protein.

The 26S proteasome is a 2.5 Mda proteolytic machine composed of 33 distinct subunits that are highly conserved among eukaryotes. It consists of a 20S proteolytic core particle (CP) and a 19S regulatory particle (RP). Protein substrates are digested within the CP, a hollow cylinder comprised of four stacked rings. The two outer rings contain seven homologous a subunits. The two inner rings are composed of seven homologous P subunits and enclose a central compartment containing six proteolytic sites that are targets for natural and synthetic proteasome inhibitors. Substrates enter the proteasome through a gated pore formed by the interlacing N termini of the alpha subunits. The gate is designed to inhibit nonspecific degradation of cellular proteins, however through the activities of the 19S regulatory particle, the gate can be opened. The 19S is composed of two subcomplexes - the lid and the base - whose association is stabilized by the S5a/Rpnl0 ubiquitin-binding subunit. The lid consists of eight nonATPases (Rpn) while the base features two non-ATPases and six ATPases (Rptl-Rpt6) belonging to the AAA (ATPases Associated with a variety of cellular Activities) family. The C termini of base ATPases contain the conserved HbYX motif, which docks into specific intersubunit pockets of the 20S a-ring and triggers gate opening in a ATPdependent manner. Recognition of polyubiquitinated substrates is coordinated by the lid of the 26S proteasome, whereas the base unfolds the substrate protein in an ATPdependent manner and then translocates it into the central chamber of the 20S CP for proteolysis.

Protein degradation by ATP-dependent proteases is an important part of cellular housekeeping and for maintaining homeostasis in the cell. Its main function is disposal of misfolded, aged, or aberrant proteins. In recent years it has also been shown to be involved in various other processes throughout the cell. In eukaryotes these functions are controlled by the 26S proteasome. Degradation by the proteasome is a highly regulated and tightly controlled system in which specific tagging by ubiquitin determines the fates of cellular proteins. When this regulation or progression of degradation is disrupted, the consequences can be severe. Inhibition of protein degradation can lead to the development of disorders, many of them being . PD is the second most common neurodegenerative disorder after Alzheimer's disease, occurring in 1-2% of the population over the age of 65. There are three symptoms that are characteristic of PD: muscle rigidity, bradykinesia (slowness of motor activity), and resting tremor. Cognitive impairment is common in the late stages of the disease as well. These symptoms have been linked to a deficiency in dopamine release caused by death of dopamine releasing (DA) neurons in the substantia nigra region of the brain stem. Several clues point to α-synuclein aggregation and proteasome inhibition as important factors in PD physiology. The proteins of the synuclein family are abundantly expressed in the brain, but their functions are not well understood. The family consists of three members, α-, β-, and γ-synuclein. They are 55-62% identical and range from 127 to 140 amino acids in length. α-synuclein has been implicated in several diseases is. It is a 14.5 kDa protein, which is enriched in pre-synaptic nerve endings where it is distributed between a pool of synaptic proteins and vesicle bound proteins. Though the nature of its function is unknown, its localization to synaptic terminals and its structural conformation may provide clues. α-synuclein is natively unfolded, but it forms a α-helix upon binding negatively charged phospholipid membranes. This may be its mode of interaction with synaptic vesicles. How the regulation of dopamine release from synaptic vesicles may be controlled by α-synuclein and its possible relationship to α-synucleinopathies will be discussed later in this section.

Reference:Kwame Nyanten Mensah. Mechanisms of Proteasome Inhibition in Neurodegenerative Diseases

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