Binding immunoglobulin protein

Binding immunoglobulin protein (BiP) also known as 78 kDa glucose-regulated protein (GRP-78) or heat shock 70 kDa protein 5 (HSPA5) is a is_associated_with::protein that in humans is encoded by the HSPA5 is_associated_with::gene.

BiP is a HSP70 molecular chaperone located in the lumen of the is_associated_with::endoplasmic reticulum (ER) that binds newly synthesized proteins as they are translocated into the ER, and maintains them in a state competent for subsequent folding and is_associated_with::oligomerization. BiP is also an essential component of the translocation machinery, as well as playing a role in retrograde transport across the ER membrane of aberrant proteins destined for degradation by the is_associated_with::proteasome. BiP is an abundant protein under all growth conditions, but its synthesis is markedly induced under conditions that lead to the accumulation of unfolded polypeptides in the ER.

Function
When Chinese hamster K12 cells are starved of glucose, the synthesis of several proteins, called is_associated_with::glucose-regulated proteins (GRPs), is markedly increased. GRP78 (HSPA5), also referred to as 'immunoglobulin heavy chain-binding protein' (BiP), a member of the heat-shock protein-70 (is_associated_with::HSP70) family is involved in the folding and assembly of proteins in the endoplasmic reticulum (ER). The level of GRP78 is strongly correlated with the amount of secretory proteins (e.g. IgG) within the ER. Because so many ER proteins interact transiently with GRP78, it is presumed that it may play a key role in assisting protein transport through the cell.

Mechanism
When the nucleotide-binding domain of GRP78 interacts with ATP, its substrate-binding domain can interact with unfolded/misfolded protein. Subsequent ATP hydrolysis acts to strengthen the interaction between GRP78 and the unfolded/misfolded protein. Under these conditions, protein disulfide isomerase (PDI) can then work to promote disulfide reduction, rearrangement, and reoxidation until the correct protein conformation is achieved. ADP/ATP exchange ends the interaction of GRP78 with the protein and thus PDI's work is halted, as well.

Once the correct protein structure is achieved, it is no longer a candidate for GRP78 binding.

Interactions
Binding immunoglobulin protein has been shown to interact with is_associated_with::thyroglobulin and is_associated_with::SIL1.

Immunological Properties
Like many stress and heat shock proteins, BiP/GRP78 has potent immunological activity when released from the internal environment of the cell into the extracelluar space. Specifically, it feeds anti-inflammatory and pro-resolutory signals into immune networks, thus helping to resolve inflammation.

The mechanisms underlying BiP's immunological activity are incompletely understood. However, it has been shown that it binds to a receptor on the surface of monocytes and induces anti-inflammatory cytokine secretion dominated by IL-10, IL-1Ra, and soluble TNFR. Furthermore, it downregulates critical molecules involved in is_associated_with::T-lymphocyte activation such as is_associated_with::HLA-DR and is_associated_with::CD86. It also modulates the differentiation pathway of monocytes into dendritic cells, causing them to develop tolerogenic characteristics, which, in turn, can facilitate the development of regulatory T-lymphocytes.

The potent immunomodulatory activities of BiP/GRP78 have also been demonstrated in animal models of autoimmune disease including collagen-induced arthritis, a murine disease that resembles human rheumatoid arthritis. Prophylactic or therapeutic parenteral delivery of BiP has been shown to ameliorate clinical and histological signs of inflammatory arthritis.

Inhibitors
Inhibitors of BiP target the ATP-binding domain. is_associated_with::Honokiol, a is_associated_with::Magnolia grandiflora derivative, is a BiP inhibitor. Inducers of BiP were also found including, BiP inducer X (BIX) was identified in a screen for compounds that induce BiP expression.