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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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Nuclear Export of mRNA02:31

Nuclear Export of mRNA

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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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Nonsense-mediated mRNA Decay02:27

Nonsense-mediated mRNA Decay

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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.
Usually, Upf3 binds to an Exon Junction Complex (EJC) at mRNA splice sites. If a ribosome fully translates the mRNA,...
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Nuclear Export01:42

Nuclear Export

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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 Sorting01:34

Nuclear Protein Sorting

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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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Export of Misfolded Proteins out of the ER01:32

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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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Video Experimental Relacionado

Updated: Sep 29, 2025

Assays for the Degradation of Misfolded Proteins in Cells
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Secuestro de proteínas lectoras de metilo para la degradación de proteínas específicas nucleares

Dhanusha A Nalawansha1, Ke Li1, John Hines1

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

Journal of the American Chemical Society
|March 21, 2022
PubMed
Resumen

Los investigadores desarrollaron nuevos PROTACs secuestrando un complejo de ligasa lector de metilo-E3, expandiendo las herramientas de degradación de proteínas dirigidas. Este enfoque permite la degradación nuclear específica de las proteínas objetivo como FKBP12 y BRD2.

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Área de la Ciencia:

  • La bioquímica
  • Biología molecular
  • Descubrimiento de drogas

Sus antecedentes:

  • La degradación dirigida de proteínas (TPD) utilizando quimeras dirigidas a la proteólisis (PROTAC) es una estrategia clave para controlar las proteínas relacionadas con la enfermedad.
  • La caja de herramientas actual para TPD está limitada por la escasez de pares de ligasa:ligando E3 disponibles.

Objetivo del estudio:

  • Introducir un nuevo método para inducir la degradación de las proteínas mediante la utilización de un lector de metilo: complejo de ligasa E3.
  • Diseñar y evaluar los PROTAC que reclutan el lector de metilo L3MBTL3: complejo de ligasa E3 para la degradación proteica dirigida.

Principales métodos:

  • PROTAC diseñados y sintetizados para reclutar el lector de metilo L3MBTL3 al complejo de ligasa Cul4DCAF5 E3.
  • Se evaluó la actividad biológica de los nuevos PROTAC en la inducción de la degradación de proteínas nucleares específicas.

Principales resultados:

  • PROTAC diseñados y validados con éxito que aprovechan el complejo L3MBTL3: Cul4DCAF5.
  • Se ha demostrado la degradación nuclear específica de las proteínas diana FKBP12 y BRD2 utilizando los nuevos PROTAC.

Conclusiones:

  • El secuestro de complejos de ligasa E3 asociados al lector de metilo ofrece una estrategia generalizable para expandir el repertorio de ligasa E3 para el desarrollo de PROTAC.
  • Este enfoque amplía el potencial de la degradación proteica dirigida en el descubrimiento de fármacos.