Structural dynamics of IRE1 and its interaction with unfolded peptides

Area of Science:

• Molecular Biology
• Cellular Biology
• Biochemistry

Background:

• The unfolded protein response (UPR) is vital for maintaining endoplasmic reticulum (ER) homeostasis.
• ER stress, caused by unfolded proteins, triggers the UPR to prevent cellular damage.
• Inositol-requiring enzyme 1 (IRE1) is a key sensor and activator of the UPR, but its precise sensing mechanism is unclear.

Purpose of the Study:

• To elucidate the structural mechanism by which IRE1 senses unfolded proteins.
• To provide high-resolution structural insights into IRE1-unfolded protein interactions.
• To reconcile existing models of IRE1's role in UPR activation.

Main Methods:

• Advanced molecular modeling.
• 137 µs of atomistic molecular dynamics simulations.
• High-resolution structural analysis.

Main Results:

• IRE1's luminal domain directly interacts with unfolded peptides.
• Two distinct binding pockets at the IRE1 dimer's center were identified for unfolded peptide binding.
• BiP association with IRE1's oligomerization interface was structurally characterized, inhibiting larger complex formation.

Conclusions:

• A unified structural model for IRE1's unfolded protein sensing mechanism was proposed.
• The findings clarify how IRE1 detects ER stress and initiates the UPR.
• This research provides critical insights into the initial activation of the unfolded protein response.