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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.
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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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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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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Modification of secretory and transmembrane proteins entering the rough ER begins in the ER lumen. These modifications aid in protein folding and stabilize the acquired tertiary structure. Protein modifications in the rough ER co-occur at different stages of protein folding.
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Regulation of the Unfolded Protein Response01:31

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Inositol-requiring kinase one or IRE1 is the most conserved eukaryotic unfolded protein response (UPR) receptor. It is a type I transmembrane protein kinase receptor with a distinctive site-specific RNase activity. As the binding mechanics of the misfolded proteins with the N-terminal domain of IRE-1 are unclear, three binding models — direct, indirect, and allosteric -- are proposed for receptor activation. Nevertheless, it is known that once a misfolded protein associates with IRE1, it...
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Nuclear protein sorting regulates nucleus composition and gene expression, crucial for determining the fate of a eukaryotic cell. Hence, the entry and exit of molecules across the nuclear envelope is a tightly controlled process. Nuclear protein sorting can be inhibited by one of the following ways: 1) masking cargo signal sequences, 2) modifying the nuclear receptor's affinity for cargo, 3) controlling the nuclear pore size, 4) retaining the cargo during its transit to the cytosol or the...
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Delineating cysteine-reactive compound modulation of cellular proteostasis processes.

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Cysteine-reactive small molecules can degrade SARS-CoV-2 nsp14 by modifying cysteines. This process impacts cellular proteostasis, affecting host proteins and stress granule formation.

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Area of Science:

  • Biochemistry
  • Molecular Biology
  • Drug Discovery

Background:

  • Covalent modulators and degraders show therapeutic promise.
  • Chemoproteomics maps druggable cysteines but full cellular impacts are unclear.

Purpose of the Study:

  • To investigate the broad cellular effects of cysteine-reactive electrophilic compounds.
  • To understand the mechanism of a SARS-CoV-2 nsp14 degrader.

Main Methods:

  • Mass spectrometry-based chemoproteomics.
  • Identification and characterization of a cysteine-reactive small molecule degrader.

Main Results:

  • A novel degrader targets SARS-CoV-2 nsp14 via cysteine modification.
  • Degradation involves host protein disulfide isomerases and impacts cellular proteostasis.
  • Electrophilic compounds induce global ubiquitylation, proteasome activation, and stress granule formation.

Conclusions:

  • Cysteine-reactive electrophilic compounds have wide-ranging effects on cellular proteostasis.
  • Understanding these impacts is crucial for developing covalent drug modalities.