78 kDa glucose-regulated protein (GRP78) (GRP78)

The 78 kDa glucose-regulated protein (GRP78), also known as Binding immunoglobulin protein (BiP), is a member of the heat shock protein 70 (Hsp70) family and acts as a primary molecular chaperone within the endoplasmic reticulum (ER) (UniProt P11021). It is essential for protein folding, preventing the aggregation of misfolded proteins, and regulating the unfolded protein response (UPR) by binding to stress sensors like PERK, IRE1, and ATF6 (PubMed: 24441047). In many cancer types, GRP78 is overexpressed and can relocate to the cell surface, where it functions as a signaling receptor that promotes cell proliferation, survival, and chemoresistance (PubMed: 30108712). The C-terminal substrate-binding domain (SBD) is the functional region responsible for capturing unfolded polypeptides, and targeting this domain with small molecules or peptides can disrupt its chaperone activity, leading to ER stress-induced apoptosis in malignant cells (PubMed: 27185034). Additionally, GRP78 has been identified as a potential entry factor for various viruses, including SARS-CoV-2, highlighting its importance in infectious diseases (PubMed: 32569208). Therapeutic strategies targeting GRP78 include small molecule inhibitors like HA15 and monoclonal antibodies like PAT-SM6, which aim to exploit the protein's role in tumor survival (PubMed: 27185034, PubMed: 23543541). The protein also plays a role in neurodegenerative diseases by managing the accumulation of misfolded proteins such as alpha-synuclein or amyloid-beta (PubMed: 25267215). Beyond its chaperone function, GRP78 is involved in calcium homeostasis within the ER, further influencing cellular stress responses (PubMed: 15618525). Its presence on the cell surface (csGRP78) makes it a unique target for antibody-drug conjugates and targeted therapies in oncology (PubMed: 28652338).

Other names

Binding immunoglobulin proteinBiPHeat shock protein family A member 5HSPA5Endoplasmic reticulum lumenal Ca(2+)-binding protein grp78

Inhibition of chaperone activity by binding to the substrate-binding domain (SBD) or nucleotide-binding domain (NBD), which prevents the folding of client proteins and triggers the unfolded protein response (UPR), ultimately leading to endoplasmic reticulum (ER) stress-mediated apoptosis in cancer cells (PubMed: 27185034).