GRP78BiP

GRP78, also known as BiP (binding immunoglobulin protein), is a major chaperone of the HSP70 family located in the lumen of the endoplasmic reticulum. It assists in the folding and assembly of nascent polypeptides, prevents aggregation of misfolded proteins, and participates in ER quality control. GRP78 is a central component of the unfolded protein response (UPR) and is upregulated by ER stress to mitigate accumulation of unfolded proteins.

Localization and structure: The protein contains an N-terminal signal sequence that directs it to the ER and a C-terminal KDEL motif for retrieval to the ER. It comprises an ATPase domain and a substrate-binding domain, characteristic of HSP70 family members, enabling cycles of ATP binding and hydrolysis that regulate substrate affinity.

Function and interactions: In unstressed cells, GRP78 binds to and silences ER stress sensors such as IRE1, PERK, and ATF6. Upon accumulation of unfolded proteins, GRP78 dissociates from these sensors to activate UPR signaling, while continuing to assist in protein folding. It also participates in calcium binding and homeostasis within the ER lumen.

Clinical relevance: GRP78/BiP is frequently upregulated in conditions of ER stress and is often found on the surface of cancer cells, where it can influence signaling, invasion, and resistance to therapy. As a biomarker of ER stress and a potential therapeutic target, GRP78 is studied in oncology and neurodegenerative diseases.

Nomenclature and genetics: The protein is encoded by the HSPA5 gene and is referred to by several names, including GRP78, BiP, and HSP70-5. It belongs to the HSP70 family of molecular chaperones and shares conserved domains with other members of the family.