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Related Concept Videos

Regulation of Nuclear Protein Sorting01:45

Regulation of Nuclear Protein Sorting

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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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Before mRNAs are exported to the cytoplasm, it is crucial to check each mRNA for structural and functional integrity. Eukaryotic cells use several different mechanisms, collectively known as mRNA surveillance, to look for irregularities in mRNAs. Irregular or aberrant mRNA are rapidly degraded by various enzymes. If a defective mRNA escapes the surveillance, it would be translated into a protein which would either be non-functional or not function properly. One of the primary irregularities in...
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The Upf proteins that carry out nonsense-mediated decay (NMD) are found in all eukaryotic organisms, including humans. Each protein has an individual role, but they need to work in collaboration. Upf1 is an ATP-dependent RNA helicase that unwinds the RNA helix. Because Upf1 can unwind any RNA, Upf2 and Upf3 are required to help Upf1 discriminate between nonsense and normal mRNAs.
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Nuclear Export01:42

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The nucleus restricts several proteins within and allows others to pass. The restricted proteins possess a nuclear retention sequence or NRS, anchoring them to the nuclear lamins and preventing their transport to the cytosol. The non-restricted proteins, after their synthesis, are transported to their site of action, such as the cytosol or other organelles, with the help of nuclear export signals or NES.
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Nuclear protein sorting is the selective trafficking of histones, polymerases, gene regulatory proteins into the nucleus and exporting RNAs and ribosomes to the cytosol. It is a tightly controlled process that regulates gene expression within a cell.
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After folding, the ER assesses the quality of secretory and membrane proteins. The correctly folded proteins are cleared by the calnexin cycle for transport to their final destination, while misfolded proteins are held back in the ER lumen. The ER chaperones attempt to unfold and refold the misfolded proteins but sometimes fail to achieve the correct native conformation. Such terminally misfolded proteins are then exported to the cytosol by ER-associated degradation or ERAD pathway for...
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Updated: Sep 29, 2025

Assays for the Degradation of Misfolded Proteins in Cells
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Hijacking Methyl Reader Proteins for Nuclear-Specific Protein Degradation.

Dhanusha A Nalawansha1, Ke Li1, John Hines1

  • 1Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, Connecticut 06511, United States.

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|March 21, 2022
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Researchers developed novel PROTACs by hijacking a methyl reader-E3 ligase complex, expanding targeted protein degradation tools. This approach enables nuclear-specific degradation of target proteins like FKBP12 and BRD2.

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Area of Science:

  • Biochemistry
  • Molecular Biology
  • Drug Discovery

Background:

  • Targeted protein degradation (TPD) using Proteolysis-Targeting Chimeras (PROTACs) is a key strategy for controlling disease-related proteins.
  • The current toolbox for TPD is limited by the scarcity of available E3 ligase:ligand pairs.

Purpose of the Study:

  • To introduce a novel method for inducing protein degradation by utilizing a methyl reader:E3 ligase complex.
  • To design and evaluate PROTACs that recruit the L3MBTL3 methyl reader:E3 ligase complex for targeted protein degradation.

Main Methods:

  • Designed and synthesized PROTACs to recruit the L3MBTL3 methyl reader to the Cul4DCAF5 E3 ligase complex.
  • Assessed the biological activity of the novel PROTACs in inducing nuclear-specific protein degradation.

Main Results:

  • Successfully designed and validated PROTACs that leverage the L3MBTL3:Cul4DCAF5 complex.
  • Demonstrated nuclear-specific degradation of target proteins FKBP12 and BRD2 using the novel PROTACs.

Conclusions:

  • Hijacking methyl reader-associated E3 ligase complexes offers a generalizable strategy to expand the E3 ligase repertoire for PROTAC development.
  • This approach broadens the potential of targeted protein degradation in drug discovery.