FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W1976573258> ?p ?o ?g. }

• W1976573258 endingPage "R435" @default.
• W1976573258 startingPage "R431" @default.
• W1976573258 abstract "Attachment of lipophilic groups is a widespread modification that occurs on nearly 1,000 proteins of diverse structure and function. At least five different types of lipids can be covalently attached to proteins: fatty acids, isoprenoids, sterols, phospholipids, and glycosylphosphatidyl inositol (GPI) anchors. Proteins can contain more than one type of lipid, e.g. myristate + palmitate, palmitate + cholesterol, or farnesyl + palmitate. An important principle derived from studies of lipid-modified proteins is that not all fat is the same. Each type of lipid moiety is attached by a different lipid transferase and each modification confers distinct properties to the modified protein. The most common outcome of lipid modification is an increased affinity for membranes. However, attachment of myristoyl or prenyl groups can also promote intramolecular and intermolecular protein–protein interactions. Another key concept is reversibility. The covalent linkage between a protein and either thioester-linked palmitate or a GPI anchor can be broken by the actions of thioesterases and phospholipases, respectively. By contrast, neither myristate nor the isoprenoids farnesyl or geranylgeranyl are physically removed from a modified protein. Instead, Mother Nature has devised a clever means for some proteins to sequester these lipophilic groups within a hydrophobic cleft, effectively shielding them from the aqueous milieu. Here, I provide an overview of the structural and functional consequences for proteins containing each type of lipid modification (depicted in Figure 1). Attachment of lipophilic groups is a widespread modification that occurs on nearly 1,000 proteins of diverse structure and function. At least five different types of lipids can be covalently attached to proteins: fatty acids, isoprenoids, sterols, phospholipids, and glycosylphosphatidyl inositol (GPI) anchors. Proteins can contain more than one type of lipid, e.g. myristate + palmitate, palmitate + cholesterol, or farnesyl + palmitate. An important principle derived from studies of lipid-modified proteins is that not all fat is the same. Each type of lipid moiety is attached by a different lipid transferase and each modification confers distinct properties to the modified protein. The most common outcome of lipid modification is an increased affinity for membranes. However, attachment of myristoyl or prenyl groups can also promote intramolecular and intermolecular protein–protein interactions. Another key concept is reversibility. The covalent linkage between a protein and either thioester-linked palmitate or a GPI anchor can be broken by the actions of thioesterases and phospholipases, respectively. By contrast, neither myristate nor the isoprenoids farnesyl or geranylgeranyl are physically removed from a modified protein. Instead, Mother Nature has devised a clever means for some proteins to sequester these lipophilic groups within a hydrophobic cleft, effectively shielding them from the aqueous milieu. Here, I provide an overview of the structural and functional consequences for proteins containing each type of lipid modification (depicted in Figure 1). Proteins that are destined to be covalently modified with the 14-carbon saturated fatty acid myristate generally contain the sequence Met–Gly–X–X–X–Ser/Thr at the amino terminus. In eukaryotes, 0.5–0.8% of all proteins are predicted to be N-myristoylated. Web-based algorithms are available to analyze whether a particular amino-terminal sequence is likely to be modified, e.g. http://mendel.imp.ac.at/myristate/SUPLpredictor.htm; http://web.expasy.org/myristoylator/. After removal of the initiating Met by methionine aminopeptidase, myristate is attached to the amino-terminal Gly. No other residue can substitute for Gly at the amino terminus, and mutants with a Gly-to-Ala substitution are often used as non-myristoylated, negative controls for determining the effect of N-myristoylation on a particular protein. N-myristoylation is catalyzed by N-myristoyl transferase (NMT), a 50 kDa cytosolic enzyme that is expressed in most organisms as one or two gene products (e.g. NMT1 and NMT2 in humans). The reaction typically occurs co-translationally, and is facilitated by binding of NMT to ribosomes. However, post-translational myristoylation of proteins can occur during apoptosis, when caspase cleavage exposes a cryptic myristoylation site. In addition to the target protein, the other substrate for NMT is myristoyl-CoA. Catalysis proceeds via an ordered reaction mechanism: myristoyl CoA binds to the enzyme first, followed by the target protein to form a ternary complex. Myristate is transferred to the protein, CoA is released, and finally the myristoylated protein is released. The linkage between myristate and the protein is an amide bond, which is extremely stable. Myristate therefore remains attached to the modified protein throughout its lifetime and a pool of endogenous, non-myristoylated protein does not generally exist in cells. Detection methods for N-myristoylated proteins include mass spectrometric analysis of the purified protein, or analysis of proteins in cells labeled with radiolabeled fatty acids or with alkyne- or azide-linked fatty acids in combination with Cu(I)-catalyzed click chemistry. One of the major functions of myristate is to assist in directing the modified protein to membranes. A central tenet, originally established by Peitzsch and McLaughlin, is that myristate alone is not sufficiently hydrophobic to stably anchor a protein to a lipid bilayer within a cell. A second signal, either a cluster of positively charged amino acids or hydrophobic residues or a covalently attached palmitate moiety, is required for stable membrane binding. Polybasic domains within myristoylated proteins interact electrostatically with negatively charged phospholipids (typically phosphatidylserine or phosphatidylinositolphosphates) that are enriched on the cytoplasmic leaflets of the plasma membrane and intracellular membranes. Proteins that utilize this type of ‘myristate+basic’ motif to achieve membrane binding include c-Src, HIV-1 Gag, MARCKS, and hisactophilin (Table 1). For the small G protein Arf1, membrane association is enhanced when hydrophobic residues in the amino-terminal helix cooperate with myristate. The second signal for membrane binding of myristoylated proteins, such as Src family kinases, several Gα subunits, and A-kinase anchoring proteins (AKAPs), is provided by palmitate, which is attached to one or more cysteine residues within the amino-terminal region. Interaction of a myristoylated protein with a particular membrane can also be indirect. For example, UNC119 proteins bind a subset of N-myristoylated proteins and function as chaperones to deliver these proteins to distinct membrane structures such as the rod outer segment or cilia.Table 1Representative lipid-modified proteinsLipid 1Lipid 2ProteinLocalizationNotesMyristateProtein kinase A, catalytic subunitCytosolicMyristate is sequestered in a hydrophobic cleft within the proteinMyristateMARCKSPlasma membrane/cytoskeletonPhosphorylation within the polybasic motif releases MARCKS from the membraneMyristateARF1Golgi<-->cytosolGTP/GDP binding induces a myristoyl switchMyristatec-SrcPlasma membrane/endosomesBinds to membranes via a myristate+basic motifMyristatePalmitateSrc family kinases (SFKs)Plasma membrane/endosomesSFKs are acylated with one or two palmitates in addition to myristateMyristatePalmitateGα subunitsPlasma membrane/cytosolAssociate with Gβγ subunitsMyristatePalmitateAKAPsPlasma membrane/intracellular organellesScaffolding proteins for protein kinase APalmitateTransferrin receptorPlasma membraneTransmembrane proteinPalmitateGPCRsPlasma membraneTransmembrane proteins; palmitate regulates cell-surface delivery, stability and signalingPalmitatePSD95Postsynaptic density (PSD)Scaffolding protein that concentrates receptors in the PSDPalmitateCholesterolHedgehogs (Sonic, Indian, Desert)Secretory pathway, extracellular spaceSecreted morphogens involved in embryo patterning and tumorigenesisPalmitoleateWntsSecretory pathway, extracellular spaceSecreted morphogens involved in embryo patterning and tumorigenesisOleateGhrelinSecretory pathway, extracellular spaceAppetite-stimulating hormoneFarnesylPalmitateH-Ras, N-RasPlasma membrane, GolgiUndergo continuous cycles of palmitoylation and depalmitoylationFarnesylK-Ras4BPlasma membraneBinds to membranes via a farnesyl+basic motifFarnesylLaminBNuclear envelopeMutated in progeriaGeranylgeranylRab and Rho GTPasesPlasma membrane, Golgi, intracellular vesiclesCan be extracted from membranes by GDIsPhosphatidylethanolamineAtg8/LC3AutophagosomeRegulates double membrane formation during autophagyGPI anchorNCAMOuter leaflet of plasma membraneNeural cell adhesion moleculeGPI anchor5’ NucleotidaseOuter leaflet of plasma membraneCell surface hydrolaseGPI anchorCD55Outer leaflet of plasma membraneComplement regulatory proteinGPI anchorThy1Outer leaflet of plasma membraneCell-surface antigen Open table in a new tab Not all myristoylated proteins are membrane bound, and there are numerous examples (e.g. cAMP-dependent protein kinase, methionine sulfoxide reductase A) of cytosolic, myristoylated proteins. Myristate can be buried in a hydrophobic cleft within the modified protein, where it may play a critical role in regulating intrinsic thermal stability, enzymatic activity, and/or protein stability. In some proteins, exposure of the myristate moiety is regulated by an intramolecular ‘myristoyl-switch’ that allows the protein to undergo reversible membrane binding (Figure 1). The switch can be triggered by binding of ligands or drugs or by protein multimerization, thereby regulating the distribution of the modified protein between cytosolic and membrane-bound states. Attachment of the 16-carbon fatty acid palmitate to proteins is a common, post-translational modification. Detection methods include radiolabeling of cells with 3H- or 125I-iodo fatty acids, acylbiotin exchange, mass spectrometry, or click chemistry techniques. Palmitoylation can occur on peripheral membrane proteins, either alone or in addition to N-myristoylation or prenylation, as well as on transmembrane proteins (Table 1). The functions of protein palmitoylation are diverse, and include membrane binding, lipid raft localization, protein trafficking and stability. Nearly all palmitoylated proteins are modified by attachment of the fatty acid to a cysteine residue via thioester linkage (S-palmitoylation). A family of cysteine-rich domain palmitoyl acyltransferases (PATs), termed DHHC for the conserved sequence Asp–His–His–Cys in the active site, is primarily responsible for S-palmitoylation of intracellular proteins in organisms ranging from yeast (7 family members in Saccharomyces cerevisiae) to humans (23 family members). DHHC PATs are multipass membrane proteins with between four and six transmembrane domains and are localized to the endoplasmic reticulum (ER), the Golgi, or the plasma membrane. Transfer of palmitate from the donor — palmitoyl CoA — to the protein substrate proceeds via an acyl enzyme intermediate. Some DHHC enzymes exhibit fatty acyl CoA chain length preferences, which may explain why longer chain fatty acids, such as stearate, oleate and arachidonate, are also found attached to proteins. There is no consensus sequence within the target protein for DHHC-mediated palmitoylation. Moreover, some proteins are apparently modified by a single DHHC, whereas others are substrates for multiple DHHC PATs. A key feature of thio-ester linked fatty acylation is that the modification is reversible. Thus, dynamic cycles of palmitoylation via PATs and depalmitoylation via palmitoyl protein thioesterases (PTEs) occur, enabling proteins to undergo reversible cycles of membrane association and dissociation within the cell. For H-Ras and N-Ras, a continuous acylation/deacylation cycle is required for these proteins to localize and signal from two different intracellular locations — the plasma membrane and the Golgi (Figure 1). When depalmitoylation is blocked, by inhibiting acyl protein thioesterase 1, H-Ras and N-Ras become mislocalized, randomly redistribute amongst all endomembranes, and signal transduction is reduced. Other palmitoylated proteins, such as R7BP and Wrch-1, use cycles of palmitoylation/depalmitoylation to translocate from the plasma membrane to the nucleus. The saturated nature of the fatty acyl chain, coupled with its chain length, enable palmitate to serve as a major driving force for proteins to associate with lipid rafts. These specialized membrane subdomains are enriched in glycosphingolipids and cholesterol, as well as phospholipids acylated with saturated fatty acids. The unique lipid composition of rafts promotes formation of a ‘liquid ordered’ domain that segregates from the bulk of the lipids in the plasma membrane. Palmitoylated proteins, such as Src family kinases, preferentially associate with and signal from rafts, and substitution with unsaturated fatty acids inhibits signaling (Figure 1). The situation is not as clear for palmitoylated transmembrane proteins: some associate with lipid rafts whereas others do not. A second mode of palmitate attachment, N-palmitoylation, occurs in Hedgehog (Hh) proteins. These secreted proteins function as morphogens and are highly active during embryonic development as well as in tumor formation in adults. Hh proteins undergo a series of unique modifications (Figure 1). Following entry into the lumen of the ER and cleavage of the signal sequence, Hh proteins are cut in half via autoprocessing. The amino-terminal 19 kDa fragment resulting from the autocleavage reaction is modified by attachment of cholesterol to its carboxyl terminus (discussed below) and palmitate to its amino-terminal Cys residue. Unlike S-palmitoylated proteins, the linkage between palmitate and Hh is an amide bond. The enzyme that catalyzes N-palmitoylation of Hh proteins is Hedgehog acyltransferase (Hhat), a multipass membrane protein that is a member of the membrane bound O-acyl transferase (MBOAT) family. Palmitoylation of Hh by Hhat is essential for its activity during development. In addition, Hhat activity is required for Hh signaling in tumorigenesis, and specific inhibitors of Hhat that block cancer cell proliferation have recently been described. To date, Hh is the only family of proteins known to be covalently modified by cholesterol, although others have been postulated to exist. This modification occurs during autoprocessing: the 3β-hydroxyl group of cholesterol acts as a nucleophile to break a thioester intermediate formed during the autocleavage reaction. As a result, cholesterol becomes linked to the carboxy-terminal Gly of Hh via an ester bond. Cholesterol modification regulates the ability of Hh proteins to diffuse during development, and has been shown to play a role in both long-range and short-range Hh signaling. Another MBOAT family member, Porcupine (Porcn), is responsible for attaching a palmitate derivative to Wnt proteins. A monounsaturated fatty acid, palmitoleate, is linked to a Ser residue that is conserved within all mammalian Wnt proteins (Ser209 in Wnt3a; Table 1). Attachment of palmitoleate is required for three steps in Wnt protein biogenesis: binding to Wntless, a protein that mediates Wnt intracellular transport; secretion of Wnt proteins into the extracellular milieu; and binding of Wnt to its receptor Frizzled. Small-molecule inhibitors that block Porcn-mediated Wnt modification and Wnt signaling have been reported and have recently been shown to exhibit therapeutic efficacy in treating Wnt-driven cancers. A third member of the MBOAT family, ghrelin acyltransferase (GOAT), uses an 8-carbon fatty acid, octanoate, as a substrate (Table 1). GOAT catalyzes attachment of octanoate to Ser3 of ghrelin, a secreted peptide hormone. Octanoylation of ghrelin is required for its activity as an appetite-stimulating factor. Thus, GOAT is an attractive therapeutic target for treatment of diseases such as obesity and diabetes. Farnesyl and geranylgeranyl are 15-carbon and 20-carbon isoprenoid groups, respectively, that are attached post-translationally to proteins (Table 1). The prenylation reaction occurs in the cytosol, and results in a thio-ether linkage between the isoprenoid and a cysteine residue at or near the carboxyl terminus of the modified protein. A hallmark of most prenylated proteins is the presence of a ‘CAAX’ box (Cys–aliphatic–aliphatic–X) at the carboxyl terminus, where the ‘X’ amino acid specifies whether the protein will be modified by farnesyl transferase (FTase) or geranylgeranyl transferase I (GGTase I). The two enzymes are related: both are αβ heterodimers that share the same α subunit but have a different β subunit. Prenylation enhances the interaction of the modified protein with the ER, where two additional processing steps take place. Ras converting enzyme I (RceI) proteolytically removes the ‘AAX’ sequence, then isoprenylcysteine carboxymethyltransferase (Icmt) carboxymethylates the newly generated carboxy-terminal Cys. Further modification of prenylated proteins can also occur. In the case of Ras proteins, palmitate is attached to one (N-Ras) or two (H-Ras) cysteines located upstream of the farnesylated Cys. Interestingly, proteins with a double Cys motif in their CAAX box (e.g. CCIF in a brain-specific Cdc42 variant) have recently been shown to bypass AAX processing, and instead undergo palmitoylation, resulting in tandem palmitoylation and prenylation at the two adjacent cysteines. A subclass of prenylated proteins is typified by geranylgeranylated Rab proteins, which contain CXC or CC sequences at their carboxyl termini. Both cysteines are prenylated by GGTase II, which works in concert with Rab escort protein (REP). Rab GTPases that end in CXC can also undergo carboxy-terminal carboxymethylation. The geranylgeranyl group is sufficiently hydrophobic to anchor the modified protein to a membrane, whereas farnesyl is not. Similar to myristoylated proteins, farnesylated proteins require a second signal for stable membrane interaction, typically palmitate (as in H-Ras) or a polybasic cluster (as in KRas4B). The use of two signals allows for reversible membrane association. Farnesyl+palmitate-containing proteins can be removed from the membrane by depalmitoylation, as discussed earlier for H- and N-Ras, whereas phosphorylation within the polybasic motif can reduce the electrostatic component of binding for proteins such as K-Ras4B or Rnd3 and result in membrane dissociation. Geranylgeranylated proteins such as Rab and Rho GTPases can also be removed from the membrane. In this case, the prenyl group facilitates protein–protein interactions with guanine nucleotide dissociation inhibitors (GDIs; Figure 1). GDI proteins contain a hydrophobic groove that binds and sequesters the geranylgeranyl moiety, thereby allowing GDIs to extract Rab and Rho proteins from the membrane and redistribute them into the cytosol, where they are inactivated. Protein prenylation and associated modifications are essential for normal cell function. Deficiency of FTase, Rce1 or Icmt is lethal in mice, and mutations in REP cause blindness in humans. Protein prenylation enzymes are also clinical targets in disease. For example, farnesylation is necessary in order for Ras proteins to bind to membranes and, when activated, to induce cell transformation in vitro and tumorigenesis in vivo. These findings led to the development of farnesyl transferase inhibitors (FTIs) with the goal of exploiting them as anti-cancer agents. Unfortunately, FTIs have failed to treat cancer in the clinic, primarily because K-Ras, the most commonly mutated Ras protein in human cancer, can bypass the effect of the FTI by instead undergoing geranylgeranylation. However, FTIs have proved effective in targeting progerin, a mutant form of lamin A involved in the rare premature aging disorder Hutchinson-Gilford progeria syndrome. Farnesylation of the lamin A precursor is required for a cleavage event that normally removes the farnesylated carboxy-terminal tail and allows mature lamin A to insert correctly into the nuclear lamina. The mutant progerin is not cleaved and remains farnesylated, resulting in abnormal nuclear envelope structure that leads to progeria. Treatment with FTIs has recently shown clinical efficacy both in mouse models of progeria and, importantly, in children suffering from the disease. To date, there is one known example of a protein that is attached directly to a phospholipid: the yeast protein Atg8, and its mammalian homolog LC3 (Table 1). Lipidation occurs through a series of ubiquitin-like conjugation steps catalyzed by autophagy-related (Atg) proteins. The carboxy-terminal Arg of Atg8 is cleaved by Atg4 to expose Gly at the Atg8 carboxyl terminus, which is then linked to Atg7, transferred to Atg3, and finally conjugated to the phospholipid phosphatidylethanolamine (PE) via an amide bond. These reactions occur on the newly forming autophagosome membrane and serve to regulate growth and closure of this double membrane organelle. As the autophagosome matures, PE is removed from Atg8 by the action of Atg4. Approximately 1% of all eukaryotic proteins are modified by a complex lipid structure known as the GPI anchor (Table 1). Assembly of the anchor and transfer to the protein occurs in the ER and is mediated by nearly two dozen different enzymes. The protein destined to be modified contains a carboxy-terminal recognition sequence that is cleaved and replaced with an anchor structure containing PE (which is linked to the protein carboxyl terminus), three mannoses, glucosamine, and an inositol phospholipid. The anchor can be further remodeled, by replacement of the fatty acid substituents on the inositol phospholipid with long-chain, saturated fatty acids. Loss of critical enzymes in the GPI biosynthetic pathway is lethal in organisms ranging from yeast to parasites to mice. GPI-modified proteins in the ER are recruited to COPII-coated vesicles through interaction with members of the p24 family of cargo receptors. In yeast, GPI-anchored proteins are sorted into specialized vesicles distinct from vesicles used for other secreted proteins, but this type of vesicular segregation may not occur in mammalian cells. After transfer from the ER to the Golgi and trafficking through the secretory pathway, the proteins are inserted into the outer, extracellular leaflet of the plasma membrane via the phosphatidylinositol (PI) moiety. In polarized cells, attachment of a GPI anchor generally serves as a trafficking signal to target proteins to the apical surface. The saturated nature of the fatty acids attached to the PI moiety enhances insertion of GPI-anchored proteins into lipid raft domains (Figure 1), where they participate in a wide variety of signal transduction pathways. Since the GPI anchor is covalently attached to the protein via an amide bond, and PI strongly inserts into the outer bilayer leaflet, one can view the GPI anchor as a mechanism to stably anchor a protein to the extracellular side of the plasma membrane. However, GPI-anchored proteins have been observed to ‘hop’ from one cell to another via intermembrane transfer, both in vitro and in vivo. Moreover, some GPI anchors are susceptible to cleavage in vitro by PI-specific phospholipase C, which removes the diacylglycerol group and results in release of the protein from the membrane. It is unclear whether this process also occurs in vivo and, if so, how it is regulated. The structural complexity of the GPI anchor as well as its heterogeneous nature have made it difficult to define its exact biological functions. Mother Nature has devised a wide array of options for proteins to exploit hydrophobic moieties as a means to promote protein–lipid and protein–protein interactions. The ability of lipid-modified proteins to reversibly associate with membranes provides an additional mechanism to regulate signal transduction. As our knowledge of the biochemistry and cell biology of lipid modification continues to grow, more proteins that contain these modifications will be identified and we will need to continue to try to deduce the effects of lipid attachment on protein structure and function. The technical difficulties in obtaining three-dimensional structures of lipid-modified proteins continues to be a challenge. However, highly informative structures of proteins with their lipid moieties attached have emerged (e.g. myristoylated ARF1, myristoylated recoverin, geranylgeranylated Rab bound to RabGDI, and palmitoleoylated Wnt8 bound to its receptor Frizzled). Moreover, the development of drugs that specifically inhibit protein myristoylation, palmitoylation and prenylation has provided therapeutic tools that are being exploited to attack lipidated proteins involved in pathogen-mediated infection, cancers and other disease states." @default.
• W1976573258 created "2016-06-24" @default.
• W1976573258 creator A5027044141 @default.
• W1976573258 date "2013-05-01" @default.
• W1976573258 modified "2023-10-16" @default.
• W1976573258 title "Covalent lipid modifications of proteins" @default.
• W1976573258 cites W1970161309 @default.
• W1976573258 cites W1972290108 @default.
• W1976573258 cites W1986698046 @default.
• W1976573258 cites W2007333388 @default.
• W1976573258 cites W2023342750 @default.
• W1976573258 cites W2034512365 @default.
• W1976573258 cites W2035998109 @default.
• W1976573258 cites W2050606799 @default.
• W1976573258 cites W2134844061 @default.
• W1976573258 cites W2160063693 @default.
• W1976573258 doi "https://doi.org/10.1016/j.cub.2013.04.024" @default.
• W1976573258 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/3712495" @default.
• W1976573258 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/23701681" @default.
• W1976573258 hasPublicationYear "2013" @default.
• W1976573258 type Work @default.
• W1976573258 sameAs 1976573258 @default.
• W1976573258 citedByCount "182" @default.
• W1976573258 countsByYear W19765732582013 @default.
• W1976573258 countsByYear W19765732582014 @default.
• W1976573258 countsByYear W19765732582015 @default.
• W1976573258 countsByYear W19765732582016 @default.
• W1976573258 countsByYear W19765732582017 @default.
• W1976573258 countsByYear W19765732582018 @default.
• W1976573258 countsByYear W19765732582019 @default.
• W1976573258 countsByYear W19765732582020 @default.
• W1976573258 countsByYear W19765732582021 @default.
• W1976573258 countsByYear W19765732582022 @default.
• W1976573258 countsByYear W19765732582023 @default.
• W1976573258 crossrefType "journal-article" @default.
• W1976573258 hasAuthorship W1976573258A5027044141 @default.
• W1976573258 hasBestOaLocation W19765732581 @default.
• W1976573258 hasConcept C121332964 @default.
• W1976573258 hasConcept C180577832 @default.
• W1976573258 hasConcept C55493867 @default.
• W1976573258 hasConcept C62520636 @default.
• W1976573258 hasConcept C70721500 @default.
• W1976573258 hasConcept C78458016 @default.
• W1976573258 hasConcept C86803240 @default.
• W1976573258 hasConcept C95444343 @default.
• W1976573258 hasConceptScore W1976573258C121332964 @default.
• W1976573258 hasConceptScore W1976573258C180577832 @default.
• W1976573258 hasConceptScore W1976573258C55493867 @default.
• W1976573258 hasConceptScore W1976573258C62520636 @default.
• W1976573258 hasConceptScore W1976573258C70721500 @default.
• W1976573258 hasConceptScore W1976573258C78458016 @default.
• W1976573258 hasConceptScore W1976573258C86803240 @default.
• W1976573258 hasConceptScore W1976573258C95444343 @default.
• W1976573258 hasIssue "10" @default.
• W1976573258 hasLocation W19765732581 @default.
• W1976573258 hasLocation W19765732582 @default.
• W1976573258 hasLocation W19765732583 @default.
• W1976573258 hasLocation W19765732584 @default.
• W1976573258 hasOpenAccess W1976573258 @default.
• W1976573258 hasPrimaryLocation W19765732581 @default.
• W1976573258 hasRelatedWork W1828955125 @default.
• W1976573258 hasRelatedWork W2034736453 @default.
• W1976573258 hasRelatedWork W2044499740 @default.
• W1976573258 hasRelatedWork W2061542922 @default.
• W1976573258 hasRelatedWork W2064901328 @default.
• W1976573258 hasRelatedWork W2096678084 @default.
• W1976573258 hasRelatedWork W2190176143 @default.
• W1976573258 hasRelatedWork W2319374022 @default.
• W1976573258 hasRelatedWork W3048727301 @default.
• W1976573258 hasRelatedWork W3193780050 @default.
• W1976573258 hasVolume "23" @default.
• W1976573258 isParatext "false" @default.
• W1976573258 isRetracted "false" @default.
• W1976573258 magId "1976573258" @default.
• W1976573258 workType "article" @default.