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Related Concept Videos

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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The Unfolded Protein Response01:37

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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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Endoplasmic Reticulum01:39

Endoplasmic Reticulum

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The Endoplasmic Reticulum (ER) in eukaryotic cells is a substantial network of interconnected membranes with diverse functions, from calcium storage to biomolecule synthesis. A primary component of the endomembrane system, the ER manufactures phospholipids critical for membrane function throughout the cell. Additionally, the two distinct regions of the ER specialize in the manufacture of specific lipids and proteins.
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The Endoplasmic Reticulum01:43

The Endoplasmic Reticulum

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The endoplasmic reticulum or ER makes up for more than half of the membranes in a cell and accounts for 10% of total cell volume. It is also the primary protein and lipid synthesis factory for most cell organelles, such as the Golgi apparatus, lysosomes, secretory vesicles, and the plasma membrane. Despite being the most extensive and functionally complex subcellular organelle, ER was the last to be discovered. After years of deliberation, Keith Porter and George Palade in the year 1954,...
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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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Post-translational Translocation of Proteins to the RER01:27

Post-translational Translocation of Proteins to the RER

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A sizable fraction of proteins destined for ER are first synthesized in the cell cytosol and then transported across the ER membrane–a process called post-translational translocation. Similar to cotranslationally translocated proteins, these proteins also use the Sec translocon complex to enter the ER lumen.
Targeting proteins to the ER
Hsp40 and Hsp70 chaperone molecules bind the translated proteins in the cytosol to prevent their folding. The chaperone binding helps to keep the signal...
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Visualization of Endoplasmic Reticulum Localized mRNAs in Mammalian Cells
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Protein quality control in the endoplasmic reticulum.

Ben P Phillips1, Natalia Gomez-Navarro1, Elizabeth A Miller1

  • 1MRC Laboratory of Molecular Biology, Cambridge, UK.

Current Opinion in Cell Biology
|May 15, 2020
PubMed
Summary

Cellular protein quality control pathways protect against misfolded proteins in the early secretory pathway. This review highlights new discoveries in endoplasmic reticulum targeting, substrate redistribution, and inner nuclear membrane quality control.

Keywords:
Endoplasmic reticulumProtein quality control

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Area of Science:

  • Cellular Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Misfolded and mistargeted proteins in the early secretory pathway pose significant risks to cellular health.
  • A complex network of protein quality control (PQC) pathways exists to mitigate these risks.
  • Understanding these PQC mechanisms is crucial for cell survival and function.

Purpose of the Study:

  • To review and highlight recent discoveries in cellular protein quality control mechanisms.
  • To discuss advances in understanding endoplasmic reticulum (ER) targeting fidelity and substrate redistribution.
  • To explore new findings in inner nuclear membrane (INM) quality control and ER export cargo selection.

Main Methods:

  • This review synthesizes findings from biochemical and structural studies.
  • It integrates data from various research investigating protein targeting, localization, and degradation.
  • The analysis includes a critical discussion of conflicting data regarding cargo receptor function.

Main Results:

  • Recent advances have improved understanding of ER targeting and the mechanisms for correcting mistargeted proteins.
  • New insights into quality control at the inner nuclear membrane, particularly concerning orphaned subunits, have emerged.
  • Developments in understanding cargo selection for ER export and the role of cargo receptors are presented.

Conclusions:

  • The cellular network for managing misfolded and mistargeted proteins is intricate and constantly evolving.
  • Continued research into these PQC pathways is essential for addressing cellular proteostasis.
  • Future research should focus on resolving conflicting data and exploring novel quality control mechanisms.