Binding immunoglobulin protein

Last updated
HSPA5
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases HSPA5 , BIP, GRP78, HEL-S-89n, MIF2, Binding immunoglobulin protein, heat shock protein family A (Hsp70) member 5, GRP78/Bip
External IDs OMIM: 138120 MGI: 95835 HomoloGene: 3908 GeneCards: HSPA5
Orthologs
SpeciesHumanMouse
Entrez

3309

14828

Ensembl

ENSG00000044574

ENSMUSG00000026864

UniProt

P11021

P20029

RefSeq (mRNA)

NM_005347

NM_001163434
NM_022310

RefSeq (protein)

NP_005338

NP_001156906
NP_071705

Location (UCSC) Chr 9: 125.23 – 125.24 Mb Chr 2: 34.77 – 34.78 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Binding immunoglobulin protein (BiP) also known as (GRP-78) or heat shock 70 kDa protein 5 (HSPA5) or (Byun1) is a protein that in humans is encoded by the HSPA5 gene. [5] [6]

BiP 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 and plays 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.

Structure

BiP contains two functional domains: a nucleotide-binding domain (NBD) and a substrate-binding domain (SBD). The NBD binds and hydrolyzes ATP, and the SBD binds polypeptides. [7]

The NBD consists of two large globular subdomains (I and II), each further divided into two small subdomains (A and B). The subdomains are separated by a cleft where the nucleotide, one Mg2+, and two K+ ions bind and connect all four domains (IA, IB, IIA, IIB). [8] [9] [10] The SBD is divided into two subdomains: SBDβ and SBDα. SBDβ serves as a binding pocket for client proteins or peptide and SBDα serves as a helical lid to cover the binding pocket. [11] [12] [13] An inter-domain linker connects NBD and SBD, favoring the formation of an NBD–SBD interface. [7]

Mechanism

The activity of BiP is regulated by its allosteric ATPase cycle: when ATP is bound to the NBD, the SBDα lid is open, which leads to the conformation of SBD with low affinity to substrate. Upon ATP hydrolysis, ADP is bound to the NBD and the lid closes on the bound substrate. This creates a low off rate for high-affinity substrate binding and protects the bound substrate from premature folding or aggregation. Exchange of ADP for ATP results in the opening of the SBDα lid and subsequent release of the substrate, which then is free to fold. [14] [15] [16] The ATPase cycle can be synergistically enhanced by protein disulfide isomerase (PDI), [17] and its cochaperones. [18]

Function

When K12 cells are starved of glucose, the synthesis of several proteins, called glucose-regulated proteins (GRPs), is markedly increased. GRP78 (HSPA5), also referred to as 'immunoglobulin heavy chain-binding protein' (BiP), is a member of the heat-shock protein-70 (HSP70) family and involved in the folding and assembly of proteins in the ER. [6] The level of BiP is strongly correlated with the amount of secretory proteins (e.g. IgG) within the ER. [19]

Substrate release and binding by BiP facilitates diverse functions in the ER such as folding and assembly of newly synthesized proteins, binding to misfolded proteins to prevent protein aggregation, translocation of secretory proteins, and initiation of the UPR. [9]

Protein folding and holding

BiP can actively fold its substrates (acting as a foldase) or simply bind and restrict a substrate from folding or aggregating (acting as a holdase). Intact ATPase activity and peptide binding activity are required to act as a foldase: temperature-sensitive mutants of BiP with defective ATPase activity (called class I mutations) and mutants of BiP with defective peptide binding activity (called class II mutations) both fail to fold carboxypeptidase Y (CPY) at non-permissive temperature. [20]

ER translocation

As an ER molecular chaperone, BiP is also required to import polypeptide into the ER lumen or ER membrane in an ATP-dependent manner. ATPase mutants of BiP were found to cause a block in translocation of a number of proteins (invertase, carboxypeptidase Y, a-factor) into the lumen of the ER. [21] [22] [23]

ER-associated degradation (ERAD)

BiP also plays a role in ERAD. The most studied ERAD substrate is CPY*, a constitutively misfolded CPY completely imported into the ER and modified by glycosylation. BiP is the first chaperone that contacts CPY* and is required for CPY* degradation. [24] ATPase mutants (including allosteric mutants) of BiP have been shown to significantly slow down the degradation rate of CPY*. [25] [26]

UPR pathway

BiP is both a target of the ER stress response, or UPR, and an essential regulator of the UPR pathway. [27] [28] During ER stress, BiP dissociates from the three transducers (IRE1, PERK, and ATF6), effectively activating their respective UPR pathways. [29] As a UPR target gene product, BiP is upregulated when UPR transcription factors associate with the UPR element in BiP’s DNA promoter region. [30]

Interactions

BiP’s ATPase cycle is facilitated by its co-chaperones, both nucleotide binding factors (NEFs), which facilitate ATP binding upon ADP release, and J proteins, which promote ATP hydrolysis. [18] BiP is also a validated substrate of HYPE (Huntingtin Yeast Interacting Partner E), which can adenylate BiP at multiple residues. [31]

Conservation of BiP cysteines

BiP is highly conserved among eukaryotes, including mammals (Table 1). It is also widely expressed among all tissue types in human. [32] In the human BiP, there are two highly conserved cysteines. These cysteines have been shown to undergo post-translational modifications in both yeast and mammalian cells. [33] [34] [35] In yeast cells, the N-terminus cysteine has been shown to be sulfenylated and glutathionylated upon oxidative stress. Both modifications enhance BiP's ability to prevent protein aggregation. [33] [34] In mice cells, the conserved cysteine pair forms a disulfide bond upon activation of GPx7 (NPGPx). The disulfide bond enhances BiP's binding to denatured proteins. [36]

Table 1. Conservation of BiP in mammalian cells
Species common nameSpecies scientific nameConservation of BiPConservation of BiP's cysteineCysteine number
PrimatesHumanHomo sapiensYesYes2
MacaqueMacaca fuscataYesYes2
VervetChlorocebus sabaeusPredicted*Yes2
MarmosetCallithrix jacchusYesYes2
RodentsMouseMus musculusYesYes2
RatRattus norvegicusYesYes3
Guinea pigCavia porcellusPredictedYes3
Naked mole ratHeterocephalus glaberYesYes3
RabbitOryctolagus cuniculusPredictedYes2
Tree shrewTupaia chinensisYesYes2
UngulatesCowBos taurusYesYes2
Minke whaleBalaenoptera acutorostrata scammoniYesYes2
PigSus scrofaPredictedYes2
CarnivoresDogCanis familiarisPredictedYes2
CatFelis silvestrisYesYes3
FerretMustela putorius furoPredictedYes2
MarsupialsOpossumMonodelphis domesticaPredictedYes2
Tasmanian DevilSarcophilus harrisiiPredictedYes2
*Predicted: Predicted sequence according to NCBI protein

Clinical significance

Autoimmune disease

Like many stress and heat shock proteins, BiP has potent immunological activity when released from the internal environment of the cell into the extracellular space. [37] Specifically, it feeds anti-inflammatory and pro-resolutory signals into immune networks, thus helping to resolve inflammation. [38] The mechanisms underlying BiP's immunological activity are incompletely understood. Nonetheless, it has been shown to induce anti-inflammatory cytokine secretion by binding to a receptor on the surface of monocytes, downregulate critical molecules involved in T-lymphocyte activation, and modulate the differentiation pathway of monocytes into dendritic cells. [39] [40]

The potent immunomodulatory activities of BiP/GRP78 have also been demonstrated in animal models of autoimmune disease including collagen-induced arthritis, [41] 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. [42]

Cardiovascular disease

Upregulation of BiP has been associated with ER stress-induced cardiac dysfunction and dilated cardiomyopathy. [43] [44] BiP also has been proposed to suppress the development of atherosclerosis through alleviating homocysteine-induced ER stress, preventing apoptosis of vascular endothelial cells, inhibiting the activation of genes responsible for cholesterol/triglyceride biosynthesis, and suppressing tissue factor procoagulant activity, all of which can contribute to the buildup of atherosclerotic plaques. [45]

Some anticancer drugs, such as proteasome inhibitors, have been associated with heart failure complications. In rat neonatal cardiomyocytes, overexpression of BiP attenuates cardiomyocyte death induced by proteasome inhibition. [46]

Neurodegenerative disease

As an ER chaperone protein, BiP prevents neuronal cell death induced by ER stress by correcting misfolded proteins. [47] [48] Moreover, a chemical inducer of BiP, named BIX, reduced cerebral infarction in cerebral ischemic mice. [49] Conversely, enhanced BiP chaperone function has been strongly implicated in Alzheimer’s disease. [45] [50]

Metabolic disease

BiP heterozygosity is proposed to protect against high fat diet-induced obesity, type 2 diabetes, and pancreatitis by upregulating protective ER stress pathways. BiP is also necessary for adipogenesis and glucose homeostasis in adipose tissues. [51]

Infectious disease

Prokaryotic BiP orthologs were found to interact with key proteins such as RecA, which is vital to bacterial DNA replication. As a result, these bacterial Hsp70 chaperones represent a promising set of targets for antibiotic development. Notably, the anticancer drug OSU-03012 re-sensitized superbug strains of Neisseria gonorrhoeae to several standard-of-care antibiotics. [50] Meanwhile, a virulent strain of Shiga toxigenic Escherichia coli undermines host cell survival by producing AB5 toxin to inhibit host BiP. [45] In contrast, viruses rely on host BiP to successfully replicate, largely by infecting cells through cell-surface BiP, stimulating BiP expression to chaperone viral proteins, and suppressing the ER stress death response. [50] [52]

Notes

Related Research Articles

Endoplasmic reticulum Cell organelle that synthesizes, folds and processes proteins

The endoplasmic reticulum (ER) is, in essence, the transportation system of the eukaryotic cell, and has many other important functions such as protein folding. It is a type of organelle made up of two subunits – rough endoplasmic reticulum (RER), and smooth endoplasmic reticulum (SER). The endoplasmic reticulum is found in most eukaryotic cells and forms an interconnected network of flattened, membrane-enclosed sacs known as cisternae, and tubular structures in the SER. The membranes of the ER are continuous with the outer nuclear membrane. The endoplasmic reticulum is not found in red blood cells, or spermatozoa.

Chaperone (protein)

Chaperone proteins participate in the folding of over half of all mammalian proteins. In molecular biology, molecular chaperones are proteins that assist the conformational folding or unfolding and the assembly or disassembly of other macromolecular structures. Chaperones are present when the macromolecules perform their normal biological functions and have correctly completed the processes of folding and/or assembly. The chaperones are concerned primarily with protein folding. The first protein to be called a chaperone assists the assembly of nucleosomes from folded histones and DNA and such assembly chaperones, especially in the nucleus, are concerned with the assembly of folded subunits into oligomeric structures.

Hsp70 Heat shock protein

The 70 kilodalton heat shock proteins are a family of conserved ubiquitously expressed heat shock proteins. Proteins with similar structure exist in virtually all living organisms. Intracellularly localized Hsp70s are an important part of the cell's machinery for protein folding, performing chaperoning functions, and helping to protect cells from the adverse effects of physiological stresses. Additionally, membrane-bound Hsp70s have been identified as a potential target for cancer therapies and their extracellularly localized counterparts have been identified as having both membrane-bound and membrane-free structures.

Hsp90 Heat shock proteins with a molecular mass around 90kDa

Hsp90 is a chaperone protein that assists other proteins to fold properly, stabilizes proteins against heat stress, and aids in protein degradation. It also stabilizes a number of proteins required for tumor growth, which is why Hsp90 inhibitors are investigated as anti-cancer drugs.

Calnexin

Calnexin (CNX) is a 67kDa integral protein of the endoplasmic reticulum (ER). It consists of a large N-terminal calcium-binding lumenal domain, a single transmembrane helix and a short, acidic cytoplasmic tail.

HSPA8

Heat shock 70 kDa protein 8 also known as heat shock cognate 71 kDa protein or Hsc70 or Hsp73 is a heat shock protein that in humans is encoded by the HSPA8 gene on chromosome 11. As a member of the heat shock protein 70 family and a chaperone protein, it facilitates the proper folding of newly translated and misfolded proteins, as well as stabilize or degrade mutant proteins. Its functions contribute to biological processes including signal transduction, apoptosis, autophagy, protein homeostasis, and cell growth and differentiation. It has been associated with an extensive number of cancers, neurodegenerative diseases, cell senescence, and aging.

The unfolded protein response (UPR) is a cellular stress response related to the endoplasmic reticulum (ER) stress. It has been found to be conserved between all mammalian species, as well as yeast and worm organisms.

Heat shock protein 47

Heat shock protein 47, also known as SERPINH1 is a serpin which serves as a human chaperone protein for collagen.

Adenylylation Biological process

Adenylylation, more commonly known as AMPylation, is a process in which an adenosine monophosphate (AMP) molecule is covalently attached to the amino acid side chain of a protein. This covalent addition of AMP to a hydroxyl side chain of the protein is a posttranslational modification. Adenylylation involves a phosphodiester bond between a hydroxyl group of the molecule undergoing adenylylation, and the phosphate group of the adenosine monophosphate nucleotide. Enzymes that are capable of catalyzing this process are called AMPylators.

HSPA1A

Heat shock 70 kDa protein 1, also termed Hsp72, is a protein that in humans is encoded by the HSPA1A gene. As a member of the heat shock protein 70 family and a chaperone protein, it facilitates the proper folding of newly translated and misfolded proteins, as well as stabilize or degrade mutant proteins. In addition, Hsp72 also facilitates DNA repair. Its functions contribute to biological processes including signal transduction, apoptosis, protein homeostasis, and cell growth and differentiation. It has been associated with an extensive number of cancers, neurodegenerative diseases, cell senescence and aging, and inflammatory diseases such as Diabetes mellitus type 2 and rheumatoid arthritis.

HSP90B1

Heat shock protein 90kDa beta member 1 (HSP90B1), known also as endoplasmin, gp96, grp94, or ERp99, is a chaperone protein that in humans is encoded by the HSP90B1 gene.

ATF6

Activating transcription factor 6, also known as ATF6, is a protein that, in humans, is encoded by the ATF6 gene and is involved in the unfolded protein response.

DNA damage-inducible transcript 3

DNA damage-inducible transcript 3, also known as C/EBP homologous protein (CHOP), is a pro-apoptotic transcription factor that is encoded by the DDIT3 gene. It is a member of the CCAAT/enhancer-binding protein (C/EBP) family of DNA-binding transcription factors. The protein functions as a dominant-negative inhibitor by forming heterodimers with other C/EBP members, preventing their DNA binding activity. The protein is implicated in adipogenesis and erythropoiesis and has an important role in the cell's stress response.

HSPA1L

Heat shock 70 kDa protein 1L is a protein that in humans is encoded by the HSPA1L gene on chromosome 6. As a member of the heat shock protein 70 (Hsp70) family and a chaperone protein, it facilitates the proper folding of newly translated and misfolded proteins, as well as stabilize or degrade mutant proteins. Its functions contribute to biological processes including signal transduction, apoptosis, protein homeostasis, and cell growth and differentiation. It has been associated with an extensive number of cancers, neurodegenerative diseases, cell senescence and aging, and Graft-versus-host disease.

DNAJC3

DnaJ homolog subfamily C member 3 is a protein that in humans is encoded by the DNAJC3 gene.

DNAJB11

DnaJ homolog subfamily B member 11 is a protein that in humans is encoded by the DNAJB11 gene.

SIL1

Nucleotide exchange factor SIL1 is a protein that in humans is encoded by the SIL1 gene.

Chaperone DnaJ

In molecular biology, chaperone DnaJ, also known as Hsp40, is a molecular chaperone protein. It is expressed in a wide variety of organisms from bacteria to humans.

Beta cells are heavily engaged in the synthesis and secretion of insulin. They are therefore particularly sensitive to endoplasmic reticulum (ER) stress and the subsequent unfolded protein response (UPR). Severe or prolonged episodes of ER stress can lead to the death of beta cells, which can contribute to the development of both Type I and Type II diabetes.

GrpE

GrpE is a bacterial nucleotide exchange factor that is important for regulation of protein folding machinery, as well as the heat shock response. It is a heat-inducible protein and during stress it prevents unfolded proteins from accumulating in the cytoplasm. Accumulation of unfolded proteins in the cytoplasm can lead to cell death.

References

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