The document discusses the aging and degradation of proteins. It describes the ubiquitin-proteasome system, which involves three main steps: 1) identification of proteins for degradation, 2) marking proteins with ubiquitin, and 3) degrading proteins in the proteasome. Misfolded proteins in the endoplasmic reticulum can be targeted through ER-associated degradation or lysosomal degradation. ERAD involves retrograde translocation of misfolded proteins from the ER to the cytosol for proteasomal degradation, while lysosomal degradation involves autophagy and digestion in phagolysosomes.
The document discusses the aging and degradation of proteins. It describes the ubiquitin-proteasome system, which involves three main steps: 1) identification of proteins for degradation, 2) marking proteins with ubiquitin, and 3) degrading proteins in the proteasome. Misfolded proteins in the endoplasmic reticulum can be targeted through ER-associated degradation or lysosomal degradation. ERAD involves retrograde translocation of misfolded proteins from the ER to the cytosol for proteasomal degradation, while lysosomal degradation involves autophagy and digestion in phagolysosomes.
The document discusses the aging and degradation of proteins. It describes the ubiquitin-proteasome system, which involves three main steps: 1) identification of proteins for degradation, 2) marking proteins with ubiquitin, and 3) degrading proteins in the proteasome. Misfolded proteins in the endoplasmic reticulum can be targeted through ER-associated degradation or lysosomal degradation. ERAD involves retrograde translocation of misfolded proteins from the ER to the cytosol for proteasomal degradation, while lysosomal degradation involves autophagy and digestion in phagolysosomes.
Selective post-translational proteolysis is a crucial mechanism in cellular
regulation, allowing cells to control the levels of specific proteins based on their functional requirements. The process involves the degradation of target proteins in a selective and controlled manner. The Ubiquitin/Proteasome system is a key player in this process, consisting of three main steps: identification of the protein to be degraded, marking it by ubiquitination, and delivering it to the proteasome for degradation. 1. Identification of Proteins for Degradation: The cell identifies proteins for degradation based on various signals. These signals can be intrinsic, such as specific hydrophobic sequences or motifs within the protein, or acquired through processes like phosphorylation, binding to adaptor proteins, or damage due to fragmentation, oxidation, or aging. Proteins required at specific stages of the cell cycle are rapidly degraded once they have completed their functions. 2. Ubiquitination Process: Ubiquitin, a highly conserved 76 amino acid protein, is covalently attached to lysine side chains of the target protein via an ATP-dependent pathway involving three separate enzymes. The ubiquitin-activating enzyme (E1) uses ATP hydrolysis energy to attach ubiquitin to itself through a high-energy covalent bond (a thioester). E1 then passes this activated ubiquitin to one of a set of ubiquitin-conjugating (E2) enzymes, each of which acts in conjunction with a set of accessory (E3) proteins called ubiquitin ligases.
Ubiquitination can occur as monoubiquitination (one ubiquitin molecule
added to one substrate protein residue), multi-ubiquitination (one ubiquitin molecule added to multiple substrate residues), or Polyubiquitination, which involves attaching a chain of ubiquitin molecules to one or more lysine residues. Chains linked via Lys48 (K48) target proteins for proteasomal degradation, while those linked via Lys63 (K63) are implicated in DNA repair and activation of protein kinases. 3. Proteasomes: Ubiquitinated proteins are degraded by the 26S proteasome, a large complex present in the cytoplasm and nucleus but not in the endoplasmic reticulum (ER). It consists of two main subcomplexes: the 20S core particle and regulatory particles on either end of the barrel. The 20S core particle contains four rings, with three of the seven subunits in each ring having protease activities, each with different substrate specificities. The regulatory particles recognize ubiquitinated proteins, remove the ubiquitin chain, and unfold the protein, allowing it to enter the core particle for degradation. The proteasome plays a crucial role in maintaining cellular homeostasis by regulating the turnover of specific proteins involved in various cellular processes, including cell cycle progression, DNA repair, and immune response.
Misfolding of proteins in the endoplasmic reticulum (ER) is a common cellular
challenge that needs to be addressed to maintain proper cellular function. When proteins fail to fold correctly in the ER, they can be targeted for degradation through various cellular pathways, including ER-associated degradation (ERAD) and lysosomal degradation.
1. ER-Associated Degradation (ERAD): ERAD is a quality control mechanism
that identifies and eliminates misfolded or unassembled proteins in the ER. Initially, it was believed that the ER contained proteases capable of degrading misfolded proteins locally. However, it is now understood that ERAD involves retrograde translocation of misfolded proteins from the ER lumen to the cytosol for subsequent degradation by the proteasome. Proteins selected for ERAD are usually tagged with ubiquitin, marking them for recognition by the proteasome. 2. Lysosomal degradation: Lysosomes contain a variety of hydrolytic enzymes, including proteases, nucleases, lipases, and glycosidases. These enzymes function optimally in the acidic environment of the lysosome. Lysosomes take up cellular proteins by fusion with autophagosomes, which are formed by the enclosure of areas of cytoplasm or organelles (e.g., a mitochondrion) in fragments of the endoplasmic reticulum. This fusion yields a phagolysosome, which digests the contents of the autophagosome.