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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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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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Molecular Chaperones and Protein Folding03:00

Molecular Chaperones and Protein Folding

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The native conformation of a protein is formed by interactions between the side chains of its constituent amino acids. When the amino acids cannot form these interactions, the protein cannot fold by itself and needs chaperones. Notably, chaperones do not relay any additional information required for the folding of polypeptides; the native conformation of a protein is determined solely by its amino acid sequence. Chaperones catalyze protein folding without being a part of the folded protein.
The...
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Molecular Chaperones and Protein Folding03:00

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Regulation of the Unfolded Protein Response01:31

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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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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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Related Experiment Video

Updated: Mar 24, 2026

Using CRISPR/Cas9 Gene Editing to Investigate the Oncogenic Activity of Mutant Calreticulin in Cytokine Dependent Hematopoietic Cells
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Using CRISPR/Cas9 Gene Editing to Investigate the Oncogenic Activity of Mutant Calreticulin in Cytokine Dependent Hematopoietic Cells

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Mutant calreticulin: when a chaperone becomes intrusive.

Mario Cazzola1

  • 1FONDAZIONE ISTITUTO DI RICOVERO E CURA A CARATTERE SCIENTIFICO POLICLINICO SAN MATTEO; UNIVERSITY OF PAVIA.

Blood
|March 12, 2016
PubMed
Summary

Researchers uncovered a new mechanism in CALR-mutant myeloproliferative neoplasms (MPNs). A mutated chaperone protein constantly activates thrombopoietin (TPO) receptor signaling via MPL, defining a novel disease pathway.

Area of Science:

  • Hematology
  • Molecular Biology
  • Oncology

Background:

  • Myeloproliferative neoplasms (MPNs) are a group of blood cancers.
  • CALR mutations are a key driver in certain MPNs.
  • The precise molecular mechanisms driving CALR-mutant MPNs require further elucidation.

Purpose of the Study:

  • To unravel the molecular pathogenesis of CALR-mutant myeloproliferative neoplasms (MPNs).
  • To define a novel disease paradigm for these hematologic malignancies.

Main Methods:

  • The study integrates findings from three independent research groups (Marty et al., Chachoua et al., and Araki et al.).
  • Analysis focused on the interaction between mutant calreticulin (CALR) and the thrombopoietin (TPO) receptor (MPL).

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Defining Hsp33's Redox-regulated Chaperone Activity and Mapping Conformational Changes on Hsp33 Using Hydrogen-deuterium Exchange Mass Spectrometry
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Related Experiment Videos

Last Updated: Mar 24, 2026

Using CRISPR/Cas9 Gene Editing to Investigate the Oncogenic Activity of Mutant Calreticulin in Cytokine Dependent Hematopoietic Cells
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Main Results:

  • A mutant chaperone protein (mutant CALR) was identified as a key player.
  • This mutant chaperone constitutively activates MPL receptor signaling.
  • An abnormal interaction between mutant CALR and MPL defines a novel molecular mechanism.

Conclusions:

  • These findings establish a new disease paradigm for CALR-mutant MPNs.
  • Understanding this pathway offers potential therapeutic targets for MPNs.
  • The constitutive activation of MPL signaling by mutant CALR is central to MPN pathogenesis.