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関連する概念動画

Regulated Protein Degradation02:58

Regulated Protein Degradation

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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.
Protein degradation plays two important roles in the cells. It helps to protect cells from misfolded or damaged proteins before they lead to a...
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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.
In this pathway, the target proteins are first tagged with small proteins called ubiquitin. This involves participation of a series of enzymes including— E1 (ubiquitin-activating enzyme), E2 (ubiquitin-conjugating enzyme), and E3...
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PI3K/mTOR/AKT Signaling Pathway01:22

PI3K/mTOR/AKT Signaling Pathway

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The mammalian target of rapamycin  (mTOR) is a serine/threonine kinase that regulates growth, proliferation, and cell survival in response to hormones, growth factors, or nutrient availability. This kinase exists in two structurally and functionally distinct forms: mTOR complex 1  (mTORC1) and mTOR complex 2  (mTORC2). The first form (mTORC1) is composed of a rapamycin-sensitive Raptor and proline-rich Akt substrate, PRAS40. In contrast,  mTORC2 consists of a...
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The Unfolded Protein Response01:37

The Unfolded Protein Response

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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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Covalently Linked Protein Regulators02:04

Covalently Linked Protein Regulators

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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.
These groups modify specific amino acids in a protein....
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The Proteasome Structure01:17

The Proteasome Structure

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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.
The proteasome is an...
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USP7-based Deubiquitinase-Targeting キメラはAMPKを安定させる

Jing Liu1,2, Xiaoping Hu3, Kaixiu Luo3

  • 1Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, United States.

Journal of the American Chemical Society
|April 10, 2024
PubMed
まとめ

研究者はUSP7を使用して新しいデウビキチナーゼ標的キメラ (DUBTAC) を開発し,標的タンパク質の安定化を拡大した. これらのUSP7ベースのDUBTACはタンパク質を効果的に安定させ,潜在的な治療用途を提供します.

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Method for Measuring the Activity of Deubiquitinating Enzymes in Cell Lines and Tissue Samples

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High-Throughput Cellular Profiling of Targeted Protein Degradation Compounds Using HiBiT CRISPR Cell Lines
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Method for Measuring the Activity of Deubiquitinating Enzymes in Cell Lines and Tissue Samples
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科学分野:

  • 生物化学
  • 分子生物学
  • 薬物の発見

背景:

  • デウビキチン酵素を標的とするキメラ (DUBTACs) は,標的型タンパク質分解 (TPD) と対照的にタンパク質を安定させる.
  • 現在のDUBTACの開発は,内生的なOTUB1機能を損なう可能性のある共性リガンドを使用してOTUB1に依存しています.

研究 の 目的:

  • DUBTACの開発のための代替デウビキチナーゼとしてUSP7を探求する.
  • タンパク質安定化のためのUSP7ベースのDUBTACを作成し,評価する.
  • AMPKイソフォームを安定させるためのUSP7ベースのDUBTACを調査する.

主な方法:

  • 非共性USP7リガンドを用いたUSP7ベースのDUBTACの開発.
  • ΔF508-CFTR変異タンパク質を安定させるためのUSP7-DUBTACの評価
  • USP7を使用したAMPK DUBTACの作成とAMPKイソフォームの安定化とシグナリングの評価.

主要な成果:

  • USP7ベースのDUBTACは,OTUB1ベースのDUBTACと比較して,ΔF508-CFTR変異タンパク質を効果的に安定させました.
  • 最初のAMPK DUBTACはUSP7の非共性リガンドを用いて開発された.
  • これらの新しいAMPK DUBTACは,異なるAMPKβ同型を選択的に安定させ,AMPKシグナル伝達を強化した.

結論:

  • USP7はDUBTACの開発に効果的に利用され,OTUB1を超える選択肢を広げることができます.
  • 非共性USP7リガンドは,共性OTUB1リガンドと比較して,DUBTAC構造のためのより安全な代替案を提供します.
  • USP7ベースのAMPK DUBTACの開発は,AMPKシグナリングを調節するための新しい治療方法を提供します.