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Chaperone BiP controls ER stress sensor Ire1 through interactions with its oligomers
Sam Dawes1,2, 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.
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.
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