Proteolysis

Proteolysis is the directed degradation (digestion) of proteins by cellular enzymes called proteases or by intramolecular digestion.

Proteolysis is used by the cell for several purposes. They include:
- Removal of N-terminal methionine residues after translation.
- Removal of the signal sequence of peptides after their transport through a membrane
- Separation of viral proteins that were translated from a monocistronic mRNA
- Digestion of proteins from foods as a source of amino acids
- Conversion of predecessor-proteins (proenzymes, zymogens, prehormones) into their final structures.
- Degradation of cyclins at different stages of the cell cycle.

Proteasome

Proteasomes are complex structures inside cells that break down proteins. Ubiquitin proteasome system or ubiquitin-26S proteasome system, is a barrel-shaped multi-protein complex that can specifically digest other proteins into short polypeptides and amino acids in an ATP-driven reaction. The Ubiquitin proteasome system is essential for many cellular processes including cell cycle, signal transduction and regulation of gene expression. The importance of proteolytic degradation inside cells and the role of ubiquitin in proteolytic pathways was acknowledged in the awarding of the 2004 Nobel Prize in Chemistry to Aaron Ciechanover, Avram Hershko and Irwin Rose.

Importance of the ubiquitin proteasome system

The ubiquitin-proteasome system is the primary mechanism in eukaryotic cells for degrading unwanted and misfolded proteins. Through the cascade of E1 ubiquitin activating, E2 ubiquitin conjugating, and E3 ubiquitin ligase enzymes, ubiquitin monomers are attached sequentially to target proteins. The polyubiquitinated proteins are then recognized by the 26S proteasome, a large ATP-dependent multicatalytic protease, which removes the ubiquitin chain and degrades the proteins to short peptides. The selection and specific timing of polyubiquitination of the target proteins are conferred by different E3 ubiquitin ligases. In addition to degrading misfolded proteins, the proteasome is involved in destruction of proteins that are regulated temporally (e.g. cell cycle regulators), or by environmental factors (e.g. cholesterol synthesis regulators and several transcription factors). In plants it is also involved in circadian clocks and phytohormones signaling pathways.

Cell cycle progression is controlled by ordered action of cyclin-dependent kinases (CDKs), activated by defined cyclins, appearing for given periods in the cycle. When the function of a CDK-cyclin complex is accomplished, the associated cyclin partner becomes polyubiquitinated and destroyed by the ubiquitin-26S proteasome system. The irreversible nature of proteolysis is utilized by cells to give the cell cycle directionnality. In the cell cycle, two structurally related multicomponent ubiquitin ligases, the Anaphase-promoting complex (APC) and the Skp1/Cul1/F-box protein (SCF) complexes (SCF complex) have essential and complementary functions by temporally controlled degradation of various cell cycle proteins (See also Ubiquitin ligase). In plants, auxin signaling is mediated by auxin-induced degradation of the Aux/IAA proteins by SCFTIR1, where TIR1 is an auxin receptor.

Structure of the 26S proteasome

The 26S proteasome is used for the digestion of ubiquitin-marked proteins. It is a barrel-shaped multi-protein complex that can specifically digest other proteins into short polypeptides and amino acids in an ATP-driven reaction. The proteasome is hollow, providing an enclosed space for protein digestion, and has openings at the two ends to allow entry of the targeted protein. It is located on both sides of a cell's nuclear membrane and consists of a 20S core protease particle and two 19S regulatory particles. The 20S unit consists of 2 rings of α subunits and 2 rings of β subunits, stacked in the order αββα as a series of heptameric rings. It is about 15 nm long and 11.5 nm wide. The alpha subunits are structural, while three of the beta subunits are catalytic and exert the proteolytic activity: β1, β2 and β5. In mammals, different catalytic subunits can be induced or repressed in response to cytokines such as interferon; the different beta subunits alter the cleavage and length preferences of the proteasome.

Each 19S unit consists of a lid and a base with a 19S regulatory particle is attached to each end of the 20S core particle via its base. Some of the subunits in the base are ATPases.

The core 20S proteasome associates with different caps, including the PA28 complex; these different caps modify the activity of the proteasome. The 20S core particle is also known as the Catalytic Particle (or CP) and can exert its proteolytic activity without ubiquitin/ATP. In many mammalian cells the 20S proteasome is the most represented species and has been shown to degrade target proteins that have been oxidized or unfolded.

An Overview of the Proteosome/Ubiquitin Mechanism

- Recognition: Ubiquinated proteins dock into the 19S cap
- Dissociation: An ATP-dependent process unravels the protein and releses the ubiquitin.
- Translocation: The protein is fed into the shaft where it reaches the inner two rings responsible for proteolysis.
- Destruction: The protein is entirely degraded into 8-11 amino acid oligopeptides which are released.

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