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Related Concept Videos

The Proteasome01:13

The Proteasome

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Eukaryotic cells can degrade proteins through several pathways. One of the most important among these is the ubiquitin-proteasome pathway. It helps the cell eliminate the misfolded, damaged, or unwarranted cytoplasmic proteins in a highly specific manner.
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It is vital to regulate the activity of enzymatic as well as non-enzymatic proteins inside the cell. This can be achieved either through creating a balance between their rate of synthesis and degradation or regulating the intrinsic activity of the protein. Both these regulation mechanisms play an essential role in the normal functioning of cells.
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The Proteasome Structure01:17

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The ubiquitin-proteasome pathway is a well-known mechanism utilized by eukaryotic cells to remove cytoplasmic proteins that are misfolded, damaged, or no longer needed. In this pathway, the protein that needs to be eliminated undergoes a process called ubiquitination, where a chain of ubiquitin molecules is attached to the 48th lysine residue of the target protein. This ubiquitin modification helps the proteasome distinguish between a target protein and a healthy protein.
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Covalently Linked Protein Regulators02:04

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Proteins can undergo many types of post-translational modifications, often in response to changes in their environment. These modifications play an important role in the function and stability of these proteins. Covalently linked molecules include functional groups, such as methyl, acetyl, and phosphate groups, and also small proteins, such as ubiquitin. There are around 200 different types of covalent regulators that have been identified.
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Anaphase Promoting Complex00:50

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The stepwise destruction of specific proteins is necessary for the progression and completion of the cell cycle. Such proteins are ubiquitinated by ubiquitin ligases and then subsequently destroyed by the proteasome. The SCF (Skp1/Cullin/F-box) and the anaphase-promoting complex (APC) are two important ubiquitin ligases involved in cell cycle progression. While SCF is active throughout the cell cycle, APC gets activated during metaphase to anaphase transition. Cdc20 or Cdh1 binds to APC and...
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The ER is the hub of protein synthesis in a cell. It has robust systems to quality control protein folding and also for degradation of terminally misfolded proteins. Under normal conditions, a small proportion of misfolded proteins that cannot be salvaged need to be transported to the cytoplasm by the ER-associated degradation or ERAD pathways. However, if the ERAD cannot handle the misfolded proteins, the cell activates the unfolded protein response or UPR to adjust the protein folding...
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Combinatorial ubiquitin code degrades deubiquitylation-protected substrates.

Mai Morita1,2, Miyu Takao1,2, Honoka Tokuhisa3

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Deubiquitylase OTUD5 is modified by E3 ligases TRIP12 and UBR5, forming branched ubiquitin chains that target proteins for proteasomal degradation. This mechanism regulates signaling and protein stability.

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Area of Science:

  • Cellular Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Protein ubiquitylation is a dynamic process regulated by ubiquitin conjugation and deconjugation.
  • The fate of deubiquitylation-stabilized substrates remains unclear.
  • Branched ubiquitin chains are known to promote proteasomal degradation.

Purpose of the Study:

  • To investigate how deubiquitylation-stabilized substrates are directed for degradation.
  • To elucidate the mechanism by which OTUD5, TRIP12, and UBR5 interact to regulate protein stability.
  • To understand the role of branched ubiquitin chains in protein degradation.

Main Methods:

  • Co-modification assays of OTUD5 by TRIP12 and UBR5.
  • Analysis of K29 and K48 branched ubiquitin chain formation.
  • Assessment of proteasomal degradation rates.
  • Investigation of TNF-α-induced NF-κB signaling pathway regulation.

Main Results:

  • OTUD5 is cooperatively modified by TRIP12 and UBR5, leading to K29/K48 branched ubiquitin chain conjugation.
  • This modification accelerates proteasomal degradation of OTUD5 substrates.
  • OTUD5 cleaves K48 linkages but not K29 linkages, allowing K29 linkages to promote K48-linked chain branching.
  • TRIP12-OTUD5 antagonism regulates TNF-α-induced NF-κB signaling.

Conclusions:

  • Branched ubiquitin chains, specifically K29/K48 linkages, are crucial for targeting deubiquitylation-protected substrates for degradation.
  • The interplay between DUBs and E3 ligases, like OTUD5 and TRIP12/UBR5, dictates substrate fate.
  • This mechanism highlights the importance of branched ubiquitin chains in balancing ubiquitylation and deubiquitylation.
  • The findings provide insights into the regulation of protein turnover and signaling pathways.