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; OMA:HSPA5 - orthologs
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: 34.66 – 34.67 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Binding immunoglobulin protein (BiPS) also known as 78 kDa glucose-regulated protein (GRP-78) or heat shock 70 kDa protein 5 (HSPA5) 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

<span class="mw-page-title-main">Endoplasmic reticulum</span> Cell organelle that processes proteins

The endoplasmic reticulum (ER) is a part of a 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.

<span class="mw-page-title-main">Chaperone (protein)</span> Proteins assisting in protein folding

In molecular biology, molecular chaperones are proteins that assist the conformational folding or unfolding of large proteins or macromolecular protein complexes. There are a number of classes of molecular chaperones, all of which function to assist large proteins in proper protein folding during or after synthesis, and after partial denaturation. Chaperones are also involved in the translocation of proteins for proteolysis.

<span class="mw-page-title-main">Hsp70</span> Family of heat shock proteins

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.

<span class="mw-page-title-main">Hsp90</span> 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.

<span class="mw-page-title-main">Calnexin</span> Mammalian protein found in humans

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. In humans, calnexin is encoded by the gene CANX.

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 mammalian species, as well as yeast and worm organisms.

<span class="mw-page-title-main">Adenylylation</span> 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 post-translational 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.

<span class="mw-page-title-main">HSP90B1</span> Protein-coding gene in the species Homo sapiens

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.

<span class="mw-page-title-main">ATF6</span> Protein-coding gene in the species Homo sapiens

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.

<span class="mw-page-title-main">Valosin-containing protein</span> Protein-coding gene in the species Homo sapiens

Valosin-containing protein (VCP) or transitional endoplasmic reticulum ATPase also known as p97 in mammals and CDC48 in S. cerevisiae, is an enzyme that in humans is encoded by the VCP gene. The TER ATPase is an ATPase enzyme present in all eukaryotes and archaebacteria. Its main function is to segregate protein molecules from large cellular structures such as protein assemblies, organelle membranes and chromatin, and thus facilitate the degradation of released polypeptides by the multi-subunit protease proteasome.

<span class="mw-page-title-main">DNA damage-inducible transcript 3</span> Human protein and coding gene

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.

<span class="mw-page-title-main">EIF2AK3</span> Human protein and coding gene

Eukaryotic translation initiation factor 2-alpha kinase 3, also known as protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK), is an enzyme that in humans is encoded by the EIF2AK3 gene.

<span class="mw-page-title-main">HSPA1L</span> Protein-coding gene in the species Homo sapiens

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.

<span class="mw-page-title-main">HERPUD1</span> Protein-coding gene in the species Homo sapiens

Homocysteine-responsive endoplasmic reticulum-resident ubiquitin-like domain member 1 protein is a protein that in humans is encoded by the HERPUD1 gene.

<span class="mw-page-title-main">SIL1</span> Protein-coding gene in the species Homo sapiens

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

Proteostasis is the dynamic regulation of a balanced, functional proteome. The proteostasis network includes competing and integrated biological pathways within cells that control the biogenesis, folding, trafficking, and degradation of proteins present within and outside the cell. Loss of proteostasis is central to understanding the cause of diseases associated with excessive protein misfolding and degradation leading to loss-of-function phenotypes, as well as aggregation-associated degenerative disorders. Therapeutic restoration of proteostasis may treat or resolve these pathologies.

<span class="mw-page-title-main">Chaperone DnaJ</span> Molecular chaperone protein

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.

Hsp104 is a heat-shock protein. It is known to reverse toxicity of mutant α-synuclein, TDP-43, FUS, and TAF15 in yeast cells. Conserved in prokaryotes (ClpB), fungi, plants and as well as animal mitochondria, there is yet to see hsp104 in multicellular animals. Hsp104 is classified as a. AAA+ ATPases and a subgroup of Hsp100/Clp, because of the usage of Atp hydrolysis for structural modulation of other proteins. Hsp104 is not needed for normal cell growth but when exposed to stress there is an increase amount. Removing the aggregates without the hsp104 is insufficient there highlighting the importance of this heat shock protein and its interactions.

FIC domain protein adenylyltransferase (FICD) is an enzyme in metazoans possessing adenylylation and deadenylylation activity (also known as (de)AMPylation), and is a member of the Fic (filamentation induced by cAMP) domain family of proteins. AMPylation is a reversible post-translational modification that FICD performs on target cellular protein substrates. FICD is the only known Fic domain encoded by the metazoan genome, and is located on chromosome 12 in humans. Catalytic activity is reliant on the enzyme's Fic domain, which catalyzes the addition of an AMP (adenylyl group) moiety to the substrate. FICD has been linked to many cellular pathways, most notably the ATF6 and PERK branches of the UPR (unfolded protein response) pathway regulating ER homeostasis. FICD is present at very low basal levels in most cell types in humans, and its expression is highly regulated. Examples of FICD include HYPE (Huntingtin Yeast Interacting Partner E) in humans, Fic-1 in C. elegans, and dfic in D. melanogaster.

References

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