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Regulation of the Unfolded Protein Response

Regulation of the Unfolded Protein Response

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...

The Unfolded Protein Response

The Unfolded Protein Response

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...

Export of Misfolded Proteins out of the ER

Export of Misfolded Proteins out of the ER

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...

Protein Folding Quality Check in the RER

Protein Folding Quality Check in the RER

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...

Post-translational Translocation of Proteins to the RER

Post-translational Translocation of Proteins to the RER

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...

ER Retrieval Pathway

ER Retrieval Pathway

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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Chaperone BiP controls ER stress sensor Ire1 through interactions with its oligomers.

Sam Dawes^1,2, Nicholas Hurst¹, Gabriel Grey¹

¹School of Molecular and Cellular Biology, Faculty of Biological Sciences & Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, UK.

Life Science Alliance

|August 5, 2024

Summary

The molecular chaperone BiP directly binds to activated Ire1 oligomers, regulating its activity. This interaction helps deactivate Ire1 during endoplasmic reticulum stress recovery.

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Area of Science:

Molecular Biology
Cellular Stress Response
Protein Folding

Background:

Inositol-requiring enzyme 1 (Ire1) activation is a key step in the unfolded protein response (UPR).
Ire1 activation involves conformational and oligomeric state changes.
The endoplasmic reticulum (ER) Hsp70 molecular chaperone BiP negatively regulates Ire1 activation.

Purpose of the Study:

To elucidate the mechanism by which BiP regulates Ire1 activation.
To investigate the direct interaction between BiP and Ire1 oligomers.

Main Methods:

Biochemical assays to study protein-protein interactions.
Analysis of Ire1 luminal domain (LD) and BiP binding.
Investigating the role of ATP in BiP-Ire1 interactions.

Main Results:

BiP directly interacts with Ire1 oligomers.
Binding of unfolded proteins to Ire1-LD induces conformational changes favoring oligomerization.
These changes expose BiP binding motifs on Ire1-LD.
BiP binds to Ire1-LD oligomers in an ATP-dependent manner.
BiP and unfolded proteins synergistically control Ire1-LD oligomerization.

Conclusions:

BiP directly regulates Ire1 activation by binding to substrate-bound Ire1-LD oligomers.
This interaction is crucial for the dynamic control of Ire1 oligomerization.
BiP binding facilitates the return of Ire1 to its deactivated state, resolving ER stress.