The derivatives have significant antioxidant capacity and the powerful activity in inhibiting self. Metal ioninduced lateral aggregation of filamentous. Chelating agents also can be used to prevent metal induced protein aggregation 62,70. Challenges of protein aggregation during purification. Biopharmaceutical product stability considerations, part. Using an in vivo assay for polyglutamine repeatinduced protein aggregation in living animals, we have determined that ectopic overexpression of both human and c. These results suggest that elevation of some metal ions in the brain induces protein aggregation with the nature of the aggregation being highly ion dependent.
We should note that the critical metal ion concentration for causing aggregation of the protein depends on the metal fig. Industrial processes can result in airborne contamination such as fine dust, and water and soil contamination. Aggregation propensities of superoxide dismutase g93. Metal ions are essential for life, playing important roles in the human body.
Analyzing protein aggregation in biopharmaceuticals. A catecholamine neurotransmitter, dopamine da, is suggested to be linked to the pathology of dementia. Aggregationinduced electrochemiluminescence by metalbinding protein responsive hydrogel scaffolds hui jiang, zhaojian qin, youkun zheng, liu liu, and xuemei wang dr. Interestingly, in vitro data indicated that arseniteinduced protein aggregates can act. Protein aggregation is a biological phenomenon in which misfolded proteins aggregate i. An efficient and rapid approach for colorimetric detection of pb. Factors influencing biotherapeutic monoclonal antibody.
West indian medical journal university of the west indies. A prochelator activated by hydrogen peroxide prevents. Moreover, the derivatives are also able to complex metal ions and to inhibit metal. For the criiiprotein conjugate antigen, albumin has been suggested to be the. In recent years, it has been found that some metal ncs undergo aggregation. In the present context, this may include both reversible selfassociation and effectively irreversible aggregation. Manganese is an essential mineral, but chronic exposure to high amounts of it, such as is experienced by welders, is associated with symptoms of parkinsons disease. Pathogenic mechanisms of heavy metal inducedalzheimers. At the beginning the protein aggregates are soluble, but gradually become. A hallmark of the disease is aggregation of the protein. Structural basis of the zincinduced cytoplasmic aggregation.
Dec 21, 2010 the role of metal ions in ad and molecular mechanisms of metala. Research paper promotes protein insolubility and aging in c. Arsenite induced protein aggregation correlates with the toxicity of the. Biophysical inquiry into protein aggregation and amyloid diseases. The understanding of metal ions induced reversible aggregation based on solution electrostatics may lead to potential applications in molecular biology and medicine. To investigate the possible link between metals, protein. Effect of ions on agitation and temperatureinduced aggregation reactions of antibodies. To our best knowledge, this is the first study providing the structural basis of the zincinduced aggregation of an rbp implicated in neurological diseases. Removal of protein aggregates from biologic apis is crucial due to their potential to increase immunogenicity. Disruption of this delicate balance can expose internal.
Protein aggregation is a widespread phenomenon in cells and associated with pathological conditions. Apr 19, 2018 alzheimers disease is an increasing neurodegenerative disease in the aging population. In this study, we provide a molecular mechanism for the polymerization of sfpq that is induced by znii binding to the protein, which results in an infinite linear polymer of sfpq. Suppression of polyglutamineinduced protein aggregation in.
In the processes, heavy metals are one of the major environmental pollutants. Wang state key laboratory of bioelectronics national demonstration center for experimental biomedical engineering education. In this study, we biochemically isolated aggregationprone proteins and used computational analyses to identify characteristics that are linked to physiological and arseniteinduced aggregation in living yeast. Binding protein responsive hydrogel scaffolds hui jiang state key laboratory of bioelectronics, national demonstration center for experimental biomedical engineering education, school of biological science and medical engineering, southeast university, nanjing, 210096 p.
In addition, cu induced fibrils have been shown to have the same morphology as. Temperatureinduced unfolding, aggregation, and interaction of therapeutic monoclonal antibodies 2 full mab molecule, each consisting of a heavy and a light chain, are linked with two. While most aggregates are formed during upstream operations, and the risk for aggregate formation at the cellular level has increased as titers have increased, if unsuitable conditions are selected for downstream operations, aggregation can also occur during downstream processing. Unusual cyclodextrin derivatives as a new avenue to. Copperinduced structural conversion templates prion protein. Unusual cyclodextrin derivatives as a new avenue to modulate. Jan 04, 2010 here, we monitored the metalinduced aggregation of a. Protein analysis, metal analysis, and aggregation conditions. Platinationinduced unfolding of mbds can lead to protein aggregation. In fact, protein aggregates have been implicated in a wide variety of disease known as amyloidoses, including als, alzheimers, parkinsons and prion disease after synthesis. Metalinduced coldgelation of proteins requires two steps. Global analysis of protein aggregation in yeast during physiological.
This study investigates the use of plantderived pcs for the inhibition of metal induced protein aggregation. Arseniteinduced protein aggregation correlates with the toxicity of the. Introduction many filamentous biopolymers such as dna and protein filaments are highly charged polyelectrolytes that frequently occur in compact and ordered forms in biological. The latter case is called orthokinetic aggregation. The freezing rate as well as the method and control of thawing has been previously reported to in. There is accumulating evidence that certain metals influence the aggregation propensity. The black, lefthand bars of figure 4 show that the presence of qbp does not change the turbidity of solutions containing a. Metalmediated selfassembly of protein superstructures.
Lumry and eyring 1954 polymerization model has been used as a starting point to study protein aggregation. These protein aggregates are often correlated with diseases. After purification, protein activity was verified by a gelbased assay as described 20, 106, and metal incorporation was assessed using icpms as described previously, with minor modifications. Research paper promotes protein insolubility and aging in. Protein aggregation mechanisms, detection, and control. Metal ion induced lateral aggregation of filamentous viruses fd and m abstract we report a detailed comparison between calculations of interfilament interactions based on montecarlo simulations and experimental features of lateral aggregation of bacteriophages fd and m induced by a number of divalent metal ions. We undertook an extensive analytical approach to determine the rootcause of the increased aggregation in the affected batches. Metaltriggered structural transformations, aggregation, and. Certain ligands such as metal ions can selectively bind to the native state of proteins. Metal ioninduced lateral aggregation of filamentous viruses. Heavy metals and metalloids as a cause for protein. Protein aggregation has been recognized as one of the major challenges in the development and commercialization of successful protein or proteinbased drug products ross and wolfe, 2016, singh et al.
It was found that all metal ions induced hsa aggregation, and this effect was. Aggregation can be enhanced through shear stress e. Aggregation induced electrochemiluminescence by metal binding protein responsive hydrogel scaffolds hui jiang, zhaojian qin, youkun zheng, liu liu, and xuemei wang dr. Using traditional metal chelating agents, potential regulation of metalinduced a.
In this work, we report a study on bovine serum albumin coldgelation induced by copper or zinc ions. Interaction of albumin and fibrinogen with stainless steel. To overcome this problem, we have herein developed iminodiacetic acidmodified human serum. Valentina oliveri dipartimento di scienze chimiche, universita di catania, viale a. Protein coldgelation has recently received particular attention for its relevance in bio and food technology. Regulatory activities of dopamine and its derivatives toward. Aghalo, proteinbased sensor, was used to detect and measure protein aggregation induced by the environmental presence of heavy metals while chw128, a smallmolecule sensor, was used to detect environmental heavy metalinduced protein aggregation in mammalian cells. What are the causes of protein aggregation in biologic formulations.
To our best knowledge, this is the first study providing the structural basis of the zinc induced aggregation of an rbp implicated in neurological diseases. The disease is associated with toxic chemicals of industrial origin. We have previously demonstrated that nonselfassociating protein building blocks can oligomerize to form discrete supramolecular assemblies under the control of metal coordination. Unusual cyclodextrin derivatives as a new avenue to modulate self. Corrosion and metal release mechanisms of the biomedical stainless steel grade type 316l are at humanrelevant biological conditions not fully understood. Impact of residual impurities and contaminants on protein. The results of this study show that pcs inhibit zinc induced. Multimeric proteins with two or more subunits can become dissociated into monomers, and monomers or single peptide chain proteins can degrade into peptide fragments.
Pdf the study of the aggregation processes in presence of metal ions is an essential step. Structure of larger aggregates formed can be different. Prion protein prp misfolding and oligomerization are key pathogenic events in prion disease. Jan 14, 2019 platination induced unfolding of mbds can lead to protein aggregation. Aghalo, protein based sensor, was used to detect and measure protein aggregation induced by the environmental presence of heavy metals while chw128, a smallmolecule sensor, was used to detect environmental heavy metal induced protein aggregation in mammalian cells. Metal dyshomeostasis is reported to be a pathogenic factor in neurodeg.
Interactions of whey proteins with metal ions mdpi. Copper exposure has been linked to prion pathogenesis. Effects on metal induced protein aggregation aggregation assays of the protein b lactoglobulin a blg were carried out to investigate whether 1, 2, and 3 could inhibit. Metalinduced aggregation has only been investigated by a small number of groups, but is perhaps the only method currently available for inducing. Qbp, on the other hand, does not interfere with metalinduced a. Aug 30, 2018 the mechanism of hginduced aggregation involves direct metalprotein interactions, loss of thermal stability, partial unfolding of the nterminal domain of these proteins, and formation of disulfidebridged dimers.
Manganese promotes the aggregation and prionlike cellto. Thermal aggregation and ioninduced coldgelation of. Pdf thermal aggregation of proteins in the presence of metal ions. Metalinduced aggregation of valine capped gold nanoparticles. Aggregation, oxidation, hydrolysis use of disposable containers. The kinetics of protein aggregation has been extensively investigated. Chelating agents also can be used to prevent metalinduced protein aggregation 62,70. Aggregation of biologically important peptides and proteins.
Synergistic effects of metalinduced aggregation of human serum. Protein aggregation kinetics during protein a chromatography. Temperatureinduced unfolding, aggregation, and interaction of therapeutic monoclonal antibodies 2 full mab molecule, each consisting of a heavy and a light chain, are linked with. Aggregation of chromophoreconjugated metal np induced emission enhancement gives a large contrast ratio from severely quenched fluorescence to significantly enhanced fluorescence much higher than the original fluorescence intensity, which is superior to the conventional turnon methods based on fluorescence recovery. Thus, the products of the reactions of cisplatin with wln4, both in the absence or presence of tm, were analyzed.
Aggregates in monoclonal antibody manufacturing processes. Protein aggregation to explain this di erence, we use as an example the stability of a monoclonal antibody at low ph. Tungsteninduced denaturation and aggregation of epoetin alfa. These results suggest that elevation of some metal ions in the brain induces protein aggregation with. Clearly when mechanism 3 is operative improving the chemical stability will also reduce aggregation, and conversely attempts to improve the conformational stability of the monomer may not reduce aggregation. Mechanisms of protein aggregation current pharmaceutical biotechnology, 2009, vol. Structural implications for heavy metalinduced reversible assembly and aggregation of a protein. Effects on metalinduced protein aggregation aggregation assays of the protein b lactoglobulin a blg were carried out to investigate whether 1, 2, and 3 could inhibit. Cadmium causes misfolding and aggregation of cytosolic proteins. We should also note that pho cuta has a stable trimeric structure even under conditions of 0. Tetrathiomolybdate induces dimerization of the metalbinding. Although several agents have been recognized to block metal associated a. We also demonstrate that misfolded prps serve as seeds for templated.
Following two cases of neutralizing antibodies to epoetin alfa in an investigational clinical study, a small number of individual syringes of two drug product batches were found to contain unusually high levels of aggregation at the end of the clinical trial. Whether cadmiuminduced protein aggregates are sequestered into. Suppression of polyglutamineinduced protein aggregation. Inhibitory activity of curcumin derivatives towards metal. To overcome this problem, we have herein developed iminodiacetic acidmodified human. In nature, nearly half of all proteins are metalbinding proteins called metalloproteins. Aggregation was induced by bufferexchanging 2 mgml sod samples into pbs with or. Metal induced aggregation of valine capped gold nanoparticles. When particle aggregation is solely driven by diffusion, one refers to perikinetic aggregation. These results show that qbp itself neither induces nor prevents metalinduced a. Luminescent metal nanoclusters ncs are emerging as a new class of functional materials that have rich physicochemical properties and wide potential applications.
Protein aggregation has been recognized as one of the major challenges in the development and commercialization of successful protein or protein based drug products ross and wolfe, 2016, singh et al. Jinzhuan wang ab, kun wang a, zhenzhu zhu c, yafeng he a, changli zhang d, zijian guo a and xiaoyong wang c a state key laboratory of coordination chemistry, school of chemistry and chemical engineering, nanjing university, nanjing, 210023, p. Tungsteninduced denaturation and aggregation of epoetin. Metal ioninduced lateral aggregation of filamentous viruses fd and m jay x. Caution must be taken as the preservatives can induce protein aggregation as not all. Chemistry of the metalinduced protein aggregation can be explained by the derjaginlandauverweyoverbeek dlvo theory of intraparticle. Whether metal induced protein aggregates are sequestered to such sites remains to be investigated.
Using an in vivo assay for polyglutamine repeat induced protein aggregation in living animals, we have determined that ectopic overexpression of both human and c. Metal ions and redox balance regulate distinct amyloidlike. Aggregation of metalnanoparticleinduced fluorescence. Pdf heavy metals and metalloids as a cause for protein. We show here that secondary interactions salt bridges and hydrogen bonds can be critical in guiding the metalinduced selfassembly of proteins. Synuclein in the range of protein concentration from. In addition, cuinduced fibrils have been shown to have the same morphology as. Phytochelatins pcs are heavy metal binding peptides found in some eukaryotes. Phytochelatins inhibit the metalinduced aggregation of. Temperatureinduced unfolding, aggregation, and interaction.
Structural implications for heavy metalinduced reversible. Nov 18, 2011 tungsteninduced denaturation and aggregation of epoetin alfa during primary packaging as a cause of immunogenicity andreas seidl, 1 otmar hainzl, 1 marleen richter, 1 robert fischer, 1 stephan bohm, 2 britta deutel, 2 martin hartinger, 1 jorg windisch, 2 nicole casadevall, 3 gerard michel london, 4 and iain macdougall 5. Tetrathiomolybdate induces dimerization of the metal. In the fast aggregation regime or dlca regime, the aggregates are more. Metaltriggered structural transformations, aggregation. Alzheimers disease is an increasing neurodegenerative disease in the aging population. Pathogenic mechanisms of heavy metal inducedalzheimers disease.