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Related Concept Videos

Protein Modifications in the RER01:26

Protein Modifications in the RER

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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.
Broadly, these modifications can be categorized into four main categories — glycosylation, formation of disulfide bonds, assembly of protein subunits, and specific proteolytic cleavages like removal of signal...
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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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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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Translocation of Proteins into the Mitochondria01:19

Translocation of Proteins into the Mitochondria

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Mitochondrial precursors are translocated to the internal subcompartments via independent mechanisms involving distinct protein machineries called translocases.
Sorting of outer membrane proteins:
Mitochondrial outer membrane proteins are of two types: the transmembrane, beta-barrel porins, and the membrane-anchored, alpha-helical proteins. Beta-barrel porin precursors are translocated by the TOM complex and inserted into the outer mitochondrial membrane by the SAM complex. In contrast,...
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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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Protein Folding Quality Check in the RER01:29

Protein Folding Quality Check in the RER

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ER is the primary site for the maturation and folding of soluble and transmembrane secretory proteins. The calnexin cycle is a specific chaperone system that folds and assesses the confirmation of N-glycosylated proteins before they can exit the ER lumen. The primary players of this quality check pipeline are the lectins, ER-resident chaperones, and a glucosyl transferase enzyme. In case the calnexin system in the lumen fails to salvage a misfolded protein, it is transported to the cytoplasm...
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Updated: Mar 24, 2026

Defining Hsp33's Redox-regulated Chaperone Activity and Mapping Conformational Changes on Hsp33 Using Hydrogen-deuterium Exchange Mass Spectrometry
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ER Protein Processing Under Oxidative Stress: Implications and Prevention.

Mahmoud F Khalil1, Carlos Valenzuela1, Daniella Sisniega2

  • 1Department of Chemistry, University of Texas at El Paso, 500 W. University Ave., Chemistry and Computer Science Building 2.0202, 121 A Spiel Paso, El Paso, TX, 79968, USA.

Cell Biochemistry and Biophysics
|March 18, 2016
PubMed
Summary

Mitochondrial stress in Parkinson's and Alzheimer's disease may involve a novel pathway impacting protein folding. Ellagic acid (EA) shows potential to protect against this oxidative damage and neurodegeneration.

Keywords:
Ellagic acidNitrosative stressParkinson’s diseaseProtein aggregationProtein foldingRadical scavengers

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Area of Science:

  • Neuroscience
  • Biochemistry
  • Cell Biology

Background:

  • Mitochondrial nitrosative stress is implicated in Parkinson's and Alzheimer's disease pathogenesis.
  • A known mechanism involves protein disulfide isomerase (PDI) dysfunction, leading to protein accumulation.
  • This study explores an additional, PDI-independent pathway.

Purpose of the Study:

  • To investigate a PDI-independent mechanism of protein misfolding under oxidative stress.
  • To determine if ellagic acid (EA) can mitigate these stress-induced effects.
  • To assess the therapeutic potential of EA in neurodegenerative disease models.

Main Methods:

  • Utilized a model system to simulate mitochondrial oxidative and nitrosative stress.
  • Assessed the impact of reactive oxygen species (ROS) on disulfide bond regeneration in ER-processed proteins.
  • Evaluated the protective effects of ellagic acid (EA) on protein maturation rates.

Main Results:

  • Demonstrated a PDI-independent mechanism where ROS impairs disulfide bond regeneration.
  • Showed that ROS induces misfolded, disulfide-exposed proteins, promoting retrotranslocation.
  • Confirmed that ellagic acid (EA) rescues compromised protein maturation rates under ROS duress.

Conclusions:

  • Revealed a novel mechanism contributing to neurodegenerative disorders via ROS-induced protein misfolding.
  • Established ellagic acid (EA) as a potential prophylactic agent against oxidative/nitrosative stress-related neurodegenerative diseases.