BiPGRP78

BiPGRP78, commonly referred to as BiP or GRP78, is an endoplasmic reticulum–resident member of the HSP70 family of molecular chaperones. It is encoded by the HSPA5 gene in humans and is highly conserved among eukaryotes. The protein contains an N-terminal ATPase domain and a C-terminal substrate-binding domain, and it carries an endoplasmic reticulum retention signal at its C-terminus, typically KDEL, which maintains BiP within the ER lumen.

BiPGRP78 functions as a central chaperone in the secretory pathway, assisting in the folding, assembly, and maturation of nascent polypeptides and glycoproteins. It binds exposed hydrophobic regions of unfolded proteins, prevents aggregation, and cooperates with co-chaperones such as DNAJ family proteins and the Sec63 complex to facilitate proper folding and translocation into the ER. BiP also plays a role in ER-associated degradation (ERAD) by recognizing misfolded proteins and aiding their delivery to the degradation machinery. In addition, it contributes to calcium homeostasis and the quality control of protein folding within the ER.

Regulation of BiPGRP78 expression is a hallmark of the unfolded protein response (UPR). Under conditions of ER stress, signaling pathways mediated by IRE1, PERK, and ATF6 upregulate HSPA5 to enhance the cell’s capacity to manage misfolded proteins. Abnormal BiP levels have been linked to various diseases; overexpression is observed in several cancers and is associated with cell survival and therapy resistance, while dysregulation is also implicated in neurodegenerative and autoimmune conditions. BiPGRP78 is sometimes found at the cell surface or in extracellular contexts, where it can participate in additional interactions relevant to disease processes.