BiP is a protein. This page describes its structure, normal nervous system function, role in neurodegenerative disease, and potential as a therapeutic target.
Binding immunoglobulin protein (BiP), also known as glucose-regulated protein 78 (GRP78) or HSPA5, is a master endoplasmic reticulum (ER) chaperone and central regulator of the unfolded protein response (UPR). BiP is essential for protein folding, calcium binding, and ER stress signaling, playing critical roles in neurodegeneration where ER stress is a prominent feature.
BiP is a 70-kDa heat shock protein family member consisting of[1]:
BiP functions through an ATP-dependent chaperone cycle[2]:
BiP is the master regulator of the UPR[3]:
ER stress is a hallmark of neurodegenerative diseases[4]:
In Alzheimer's disease, BiP plays complex roles[5]:
In prion diseases[9]:
BiP binds to and regulates three UPR sensors[10]:
BiP binds to the luminal domain of IRE1:
BiP binding keeps PERK inactive:
BiP binding retains ATF6 in the ER:
Strategies to boost BiP activity[11]:
Targeting UPR pathways[12]:
Several chemical chaperones are in clinical trials[13]:
BiP levels may indicate ER stress status[14]:
BiP reporters are used in research[15]:
| Molecule | Interaction | Functional Outcome |
|---|---|---|
| IRE1 | Regulates activation | UPR sensor control |
| PERK | Regulates activation | Translation control |
| ATF6 | Regulates activation | Transcription factor release |
| Calreticulin | Collaborates in ER | Calcium binding, folding |
| Protein disulfide isomerase | Collaborates | Disulfide bond formation |
| Derlins | Retrotranslocation | ER-associated degradation |
Current research focuses on:
Haas IG, Wabl M. Immunoglobulin heavy chain binding protein. Nature. 1983. ↩︎
Mayer MP, Bukau B. Hsp70 chaperones: cellular functions and molecular mechanism. Cellular and Molecular Life Sciences. 2005. ↩︎
Bertolotti A et al. Dynamic interaction of BiP and ER stress transducers in the unfolded-protein response. Nature Cell Biology. 2000. ↩︎
Scheper W, Hoozemans JJM. The unfolded protein response in neurodegenerative diseases: a neuropathological perspective. Acta Neuropathologica. 2015. ↩︎
Hoozemans JJM et al. Activation of the unfolded protein response in Parkinson's disease. Biochemical and Biophysical Research Communications. 2007. ↩︎
Gupta MK, Taly R. BiP: a key chaperone involved in the tau pathology. Journal of Alzheimer's Disease. 2021. ↩︎
Smith HL, Mallucci GR. The unfolded protein response: triggers and modifiers in neurodegeneration. Molecular Neurodegeneration. 2020. ↩︎
Ilieva EV et al. Oxidative and endoplasmic reticulum stress interplay in sporadic amyotrophic lateral sclerosis. Brain. 2007. ↩︎
Hetz C, Soto C. Unfolding the role of protein misfolding in neurodegenerative diseases. Nature Reviews Neuroscience. 2003. ↩︎
Walter P, Ron D. The unfolded protein response: from stress pathway to homeostatic regulation. Science. 2011. ↩︎
Gupta MK et al. BiP as a therapeutic target in neurodegeneration. Trends in Pharmacological Sciences. 2021. ↩︎
Wang M, Kaufman RJ. The impact of the endoplasmic reticulum protein-folding environment on cancer development. Nature Reviews Cancer. 2014. ↩︎
Lee YS et al. Chemical chaperones for protein misfolding diseases. Pharmacology & Therapeutics. 2019. ↩︎
Lajoie P, Snapp EL. BiP/GRP78 in neurodegeneration: a chaperone at the intersection of health and disease. Developmental Cell. 2019. ↩︎
Samali A et al. Methods to monitor endoplasmic reticulum stress and the unfolded protein response. Methods in Enzymology. 2008. ↩︎