BiP is also an essential component of the translocation machinery and plays a role in retrograde transport across the ER membrane of aberrant proteins destined for degradation by the proteasome.
The subdomains are separated by a cleft where the nucleotide, one Mg2+, and two K+ ions bind and connect all four domains (IA, IB, IIA, IIB).
[7] The activity of BiP is regulated by its allosteric ATPase cycle: when ATP is bound to the NBD, the SBDα lid is open, which leads to the conformation of SBD with low affinity to substrate.
Exchange of ADP for ATP results in the opening of the SBDα lid and subsequent release of the substrate, which then is free to fold.
ATPase mutants of BiP were found to cause a block in translocation of a number of proteins (invertase, carboxypeptidase Y, a-factor) into the lumen of the ER.
[27][28] During ER stress, BiP dissociates from the three transducers (IRE1, PERK, and ATF6), effectively activating their respective UPR pathways.
[33][34] In mice cells, the conserved cysteine pair forms a disulfide bond upon activation of GPx7 (NPGPx).
[36] Like many stress and heat shock proteins, BiP has potent immunological activity when released from the internal environment of the cell into the extracellular space.
Prophylactic or therapeutic parenteral delivery of BiP has been shown to ameliorate clinical and histological signs of inflammatory arthritis.
[43][44] BiP also has been proposed to suppress the development of atherosclerosis through alleviating homocysteine-induced ER stress, preventing apoptosis of vascular endothelial cells, inhibiting the activation of genes responsible for cholesterol/triglyceride biosynthesis, and suppressing tissue factor procoagulant activity, all of which can contribute to the buildup of atherosclerotic plaques.
[51] Prokaryotic BiP orthologs were found to interact with key proteins such as RecA, which is vital to bacterial DNA replication.
Notably, the anticancer drug OSU-03012 re-sensitized superbug strains of Neisseria gonorrhoeae to several standard-of-care antibiotics.