Binding immunoglobulin protein
Encyclopedia
Binding immunoglobulin protein (BiP) also known as 78 kDa glucose-regulated protein (GRP-78) or heat shock 70 kDa protein 5 (HSPA5) is a HSP70
molecular chaperone located in the lumen of the 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 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 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. In humans, BiP is encoded by the HSPA5 gene
.
s (GRPs), is markedly increased. Hendershot et al. pointed out that one of these, GRP78 (HSPA5), also referred to as 'immunoglobulin heavy chain-binding protein' (BiP), is a member of the heat-shock protein-70 (HSP70) family and is involved in the folding and assembly of proteins in the endoplasmic reticulum (ER). Because so many ER proteins interact transiently with GRP78, it may play a key role in monitoring protein transport through the cell.
, 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.
with thyroglobulin
and SIL1
.
The mechanisms underlying BiPs immunological activity are incompletely understood. However, it binds to a receptor on the surface of monocytes and induces anti-inflammatory cytokine secretion dominated by IL-10, IL-1Ra and sTNFR . Furthermore, it downregulates critical molecules involved in T-lymphocyte activation such as HLA-DR and 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 ameliorated clinical and histological signs of inflammatory arthritis .
Hsp70
The 70 kilodalton heat shock proteins are a family of ubiquitously expressed heat shock proteins. Proteins with similar structure exist in virtually all living organisms...
molecular chaperone located in the lumen of the endoplasmic reticulum (ER
Endoplasmic reticulum
The endoplasmic reticulum is an organelle of cells in eukaryotic organisms that forms an interconnected network of tubules, vesicles, and cisternae...
) that binds newly-synthesized proteins as they are translocated
Protein targeting
Protein targeting or protein sorting is the mechanism by which a cell transports proteins to the appropriate positions in the cell or outside of it. Sorting targets can be the inner space of an organelle, any of several interior membranes, the cell's outer membrane, or its exterior via secretion...
into the ER, and maintains them in a state competent for subsequent folding
Protein folding
Protein folding is the process by which a protein structure assumes its functional shape or conformation. It is the physical process by which a polypeptide folds into its characteristic and functional three-dimensional structure from random coil....
and oligomerization
Oligomer
In chemistry, an oligomer is a molecule that consists of a few monomer units , in contrast to a polymer that, at least in principle, consists of an unlimited number of monomers. Dimers, trimers, and tetramers are oligomers. Many oils are oligomeric, such as liquid paraffin...
. 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 proteasome
Proteasome
Proteasomes are very large protein complexes inside all eukaryotes and archaea, and in some bacteria. In eukaryotes, they are located in the nucleus and the cytoplasm. The main function of the proteasome is to degrade unneeded or damaged proteins by proteolysis, a chemical reaction that breaks...
. 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. In humans, BiP is encoded by the HSPA5 gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
.
Function
When Chinese hamster K12 cells are starved of glucose, the synthesis of several proteins, called glucose-regulated proteinGlucose-regulated protein
Glucose-regulated protein is a protein in the endoplasmic reticulum in the cell.It comes in several different molecular masses, including:*Grp78 *Grp94 *Grp170 , which is a human chaperone protein...
s (GRPs), is markedly increased. Hendershot et al. pointed out that one of these, GRP78 (HSPA5), also referred to as 'immunoglobulin heavy chain-binding protein' (BiP), is a member of the heat-shock protein-70 (HSP70) family and is involved in the folding and assembly of proteins in the endoplasmic reticulum (ER). Because so many ER proteins interact transiently with GRP78, it may play a key role in monitoring protein transport through the cell.
Mechanism
When the nucleotide-binding domain of GRP78 interacts with ATPAdenosine triphosphate
Adenosine-5'-triphosphate is a multifunctional nucleoside triphosphate used in cells as a coenzyme. It is often called the "molecular unit of currency" of intracellular energy transfer. ATP transports chemical energy within cells for metabolism...
, 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
Protein disulfide isomerase
Protein disulfide isomerase or PDI is an enzyme in the endoplasmic reticulum in eukaryotes that catalyzes the formation and breakage of disulfide bonds between cysteine residues within proteins as they fold...
) 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 interactProtein-protein interaction
Protein–protein interactions occur when two or more proteins bind together, often to carry out their biological function. Many of the most important molecular processes in the cell such as DNA replication are carried out by large molecular machines that are built from a large number of protein...
with thyroglobulin
Thyroglobulin
Thyroglobulin is a 660 kDa, dimeric protein produced by and used entirely within the thyroid gland. In earlier literature, Tg was referred to as colloid....
and SIL1
SIL1
Nucleotide exchange factor SIL1 is a protein that in humans is encoded by the SIL1 gene.-Interactions:SIL1 has been shown to interact with Binding immunoglobulin protein.-External links:* -Further reading:...
.
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 BiPs immunological activity are incompletely understood. However, it binds to a receptor on the surface of monocytes and induces anti-inflammatory cytokine secretion dominated by IL-10, IL-1Ra and sTNFR . Furthermore, it downregulates critical molecules involved in T-lymphocyte activation such as HLA-DR and 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 ameliorated clinical and histological signs of inflammatory arthritis .