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Related Concept Videos

Export of Misfolded Proteins out of the ER01:32

Export of Misfolded Proteins out of the ER

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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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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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Directing Proteins to the Rough Endoplasmic Reticulum01:34

Directing Proteins to the Rough Endoplasmic Reticulum

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The organelle-specific signaling sequences direct proteins synthesized in the cytosol to their final destination like ER, mitochondria, peroxisomes, etc. Some of the proteins directed to ER are then trafficked via vesicles to other organelles within the cell or the extracellular environment through the Golgi complex. For example, the rough ER synthesizes soluble proteins for transportation to the lysosomes or secretion out of the cell. It can also synthesize transmembrane proteins that can...
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Regulation of the Unfolded Protein Response01:31

Regulation of the Unfolded Protein Response

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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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ER Retrieval Pathway01:45

ER Retrieval Pathway

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In the secretory pathway, vesicles transport proteins from one cellular compartment to another in forward transport to deliver the protein to its correct location. Occasionally, misfolded proteins and incorrect proteins escape their original compartments, and a retrieval pathway is used to return the escaped proteins to their original compartment.
The ER uses many checkpoints to prevent the entry of incorrectly folded or a resident protein as cargo onto a transport vesicle. These mechanisms...
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Tail-anchoring of Proteins in the ER Membrane01:45

Tail-anchoring of Proteins in the ER Membrane

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Tail-anchored, or TA, proteins are estimated to make up to 3-5% of membrane proteins found in the eukaryotic cell. Such proteins have a single transmembrane domain located approximately 30 amino acid residues upstream from the C-terminal end. As a result, the signal recognition particle (SRP) cannot guide a TA protein to the ER membrane for cotranslational insertion. Hence, they are integrated into the ER membrane post-translationally using their C-terminal end as the anchor. TA proteins...
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Related Experiment Video

Updated: Sep 18, 2025

Growth-based Determination and Biochemical Confirmation of Genetic Requirements for Protein Degradation in Saccharomyces cerevisiae
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SEL1L-HRD1-mediated ERAD in mammals.

Huilun Helen Wang1, Ida Biunno2,3, Shengyi Sun4

  • 1Department of Molecular Physiology and Biological Physics, University of Virginia School of Medicine, Charlottesville, VA, USA.

Nature Cell Biology
|June 25, 2025
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Summary
This summary is machine-generated.

Endoplasmic reticulum-associated degradation (ERAD) quality control clears misfolded proteins. The SEL1L-HRD1 pathway is crucial for mammalian physiology and linked to neurodevelopmental disorders.

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Growth-based Determination and Biochemical Confirmation of Genetic Requirements for Protein Degradation in Saccharomyces cerevisiae
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Area of Science:

  • Cellular Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Endoplasmic reticulum-associated degradation (ERAD) is a vital cellular quality control process.
  • It ensures endoplasmic reticulum homeostasis by degrading misfolded or unassembled proteins.
  • The SEL1L-HRD1 complex is a key mediator of ERAD in mammals.

Purpose of the Study:

  • To review the SEL1L-HRD1-mediated ERAD pathway.
  • To explore its molecular machinery, mechanism, and physiological relevance.
  • To discuss potential therapeutic strategies targeting this system.

Main Methods:

  • Literature review of ERAD research, focusing on the SEL1L-HRD1 pathway.
  • Analysis of molecular mechanisms and substrate specificity.
  • Examination of disease associations and therapeutic targets.

Main Results:

  • The SEL1L-HRD1 complex plays a fundamental role in mammalian physiology.
  • ERAD function is substrate-specific, impacting various cellular processes.
  • Mutations in the SEL1L-HRD1 complex are linked to neurodevelopmental disorders.

Conclusions:

  • The SEL1L-HRD1 ERAD pathway is essential for maintaining cellular health.
  • Dysregulation of this pathway has significant implications for human diseases.
  • Targeting the SEL1L-HRD1 system offers potential therapeutic avenues.