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Related Concept Videos

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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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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Protein Modifications in the RER01:26

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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.
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Proteins can undergo many types of post-translational modifications, often in response to changes in their environment. These modifications play an important role in the function and stability of these proteins. Covalently linked molecules include functional groups, such as methyl, acetyl, and phosphate groups, and also small proteins, such as ubiquitin. There are around 200 different types of covalent regulators that have been identified.
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Riboswitches01:56

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Riboswitches are non-coding mRNA domains that regulate the transcription and translation of downstream genes without the help of proteins. Riboswitches bind directly to a metabolite and can form unique stem-loop or hairpin structures in response to the amount of the metabolite present. They have two distinct regions – a metabolite-binding aptamer and an expression platform.
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RNA interference (RNAi) is a cellular mechanism that inhibits gene expression by suppressing its transcription or activating the RNA degradation process. The mechanism was discovered by Andrew Fire and Craig Mello in 1998 in plants. Today, it is observed in almost all eukaryotes, including protozoa, flies, nematodes, insects, parasites, and mammals. This precise cellular mechanism of gene silencing has been developed into a technique that provides an efficient way to identify and determine the...
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Related Experiment Video

Updated: Oct 25, 2025

Electrophoretic Mobility Shift Assay EMSA for the Study of RNA-Protein Interactions: The IRE/IRP Example
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Structural and molecular bases to IRE1 activity modulation.

Timothy Langlais1, Diana Pelizzari-Raymundo2,3, Sayyed Jalil Mahdizadeh4

  • 1Univ Rennes, CNRS, ISCR (Institut des Sciences Chimiques de Rennes) UMR 6226, Rennes 35042, France.

The Biochemical Journal
|August 10, 2021
PubMed
Summary

The Unfolded Protein Response pathway, regulated by Inositol Requiring Enzyme 1 (IRE1), is a therapeutic target for diseases. This review details IRE1-targeting drugs and suggests strategies for developing improved therapeutics.

Keywords:
ER stressIRE1structure activity relationship (SAR)structure-based drug design (SBDD)unfolded protein response

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Area of Science:

  • Cellular Biology
  • Molecular Biology
  • Drug Discovery

Background:

  • The Unfolded Protein Response (UPR) is a cellular adaptive mechanism crucial for maintaining endoplasmic reticulum (ER) homeostasis.
  • Inositol Requiring Enzyme 1 (IRE1) is a key ER stress sensor within the UPR pathway, conserved across evolution.
  • IRE1's role in disease pathogenesis makes it a significant therapeutic target.

Purpose of the Study:

  • To review existing drugs targeting IRE1 activity.
  • To analyze the structural mechanisms of action for these IRE1-targeting drugs.
  • To propose avenues for developing novel, superior IRE1-targeting therapeutics.

Main Methods:

  • Literature review of IRE1-targeting drugs.
  • Structural analysis of drug-IRE1 interactions.
  • Comparative analysis of drug mechanisms of action.

Main Results:

  • Several drugs targeting IRE1 catalytic activity have been identified and demonstrated efficacy in preclinical models.
  • Distinct structural modes of action exist among current IRE1-targeting drugs.
  • Analysis reveals commonalities and differences in how these drugs interact with IRE1.

Conclusions:

  • Understanding the structural basis of IRE1 inhibition is crucial for drug development.
  • Insights gained can guide the design of next-generation IRE1 inhibitors with enhanced efficacy.
  • Targeting IRE1 offers a promising therapeutic strategy for a range of diseases.