UPR proteins IRE1 and PERK switch BiP from chaperone to ER stress sensor

Area of Science:

• Molecular biology
• Cellular stress response
• Protein folding and homeostasis

Background:

• BiP (Binding immunoglobulin protein) is a key endoplasmic reticulum (ER) chaperone.
• BiP is implicated as the primary sensor for activating the unfolded protein response (UPR).
• The precise mechanisms of BiP's dual role as a chaperone and ER stress sensor remain unclear.

Purpose of the Study:

• To elucidate the mechanistic cycle of BiP function in ER stress sensing.
• To understand how BiP transitions between its chaperone and sensor roles.
• To investigate the molecular interactions governing BiP's function in the UPR.

Main Methods:

• Reconstitution of human UPR, ER stress, and BiP chaperone systems in vitro.
• Analysis of BiP interactions with UPR proteins IRE1 and PERK.
• Investigation of co-chaperone binding and ATPase activity modulation.
• Assessment of BiP dissociation from IRE1 under different nucleotide conditions (ATP vs. ADP).

Main Results:

• BiP's interaction with IRE1 and PERK luminal domains shifts its function from chaperone to ER stress sensor.
• This interaction prevents co-chaperone binding and reduces ATPase stimulation.
• Misfolded protein-dependent dissociation of BiP from IRE1 is facilitated by ATP, not ADP.
• A novel mechanistic cycle for BiP function has been identified.

Conclusions:

• BiP operates through a distinct mechanistic cycle to function as both an Hsp70 chaperone and an ER stress sensor.
• Understanding this cycle provides insight into the UPR activation pathway.
• This discovery clarifies the molecular basis of BiP's critical role in cellular homeostasis and stress response.