Interestingly, in vitro data indicated that arseniteinduced protein aggregates can act. Whether cadmiuminduced protein aggregates are sequestered into. We should note that the critical metal ion concentration for causing aggregation of the protein depends on the metal fig. Lumry and eyring 1954 polymerization model has been used as a starting point to study protein 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. West indian medical journal university of the west indies.
For the criiiprotein conjugate antigen, albumin has been suggested to be the. Protein aggregation kinetics during protein a chromatography. Copperinduced structural conversion templates prion protein. It was found that all metal ions induced hsa aggregation, and this effect was. 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. Dec 21, 2010 the role of metal ions in ad and molecular mechanisms of metala. Yet, little is known about the rules that govern protein aggregation in living cells. Apr 19, 2018 alzheimers disease is an increasing neurodegenerative disease in the aging population. Aggregationinduced electrochemiluminescence by metalbinding protein responsive hydrogel scaffolds hui jiang, zhaojian qin, youkun zheng, liu liu, and xuemei wang dr. Phytochelatins pcs are heavy metal binding peptides found in some eukaryotes. Tungsteninduced denaturation and aggregation of epoetin. 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.
Suppression of polyglutamineinduced protein aggregation in. 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. The derivatives have significant antioxidant capacity and the powerful activity in inhibiting self. Corrosion and metal release mechanisms of the biomedical stainless steel grade type 316l are at humanrelevant biological conditions not fully understood. 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.
These results show that qbp itself neither induces nor prevents metalinduced a. Metal dyshomeostasis is reported to be a pathogenic factor in neurodeg. Protein aggregation is a biological phenomenon in which misfolded proteins aggregate i. 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. Protein aggregation to explain this di erence, we use as an example the stability of a monoclonal antibody at low ph.
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. Impact of residual impurities and contaminants on protein. Biopharmaceutical product stability considerations, part. Pdf the study of the aggregation processes in presence of metal ions is an essential step. Pdf thermal aggregation of proteins in the presence of metal ions. Protein aggregation is a widespread phenomenon in cells and associated with pathological conditions. Luminescent metal nanoclusters ncs are emerging as a new class of functional materials that have rich physicochemical properties and wide potential applications. Monoclonal antibodies and other therapeutic products are well made and formulated, but they can easily be damaged if, for example, they freeze during transportation, or are exposed to light, high temperatures or vigorous agitation. Chelating agents also can be used to prevent metal induced protein aggregation 62,70. Metalinduced aggregation has only been investigated by a small number of groups, but is perhaps the only method currently available for inducing.
The latter case is called orthokinetic aggregation. 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. Analyzing protein aggregation in biopharmaceuticals. Interactions of whey proteins with metal ions mdpi. Factors influencing biotherapeutic monoclonal antibody. In addition, cu induced fibrils have been shown to have the same morphology as. Copper exposure has been linked to prion pathogenesis. Wang state key laboratory of bioelectronics national demonstration center for experimental biomedical engineering education. Synuclein in the range of protein concentration from. Phytochelatins inhibit the metalinduced aggregation of. Thermal aggregation and ioninduced coldgelation of. Tetrathiomolybdate induces dimerization of the metal.
Research paper promotes protein insolubility and aging in. Unusual cyclodextrin derivatives as a new avenue to modulate. In recent years, it has been found that some metal ncs undergo aggregation. Protein aggregation has been recognized as one of the major challenges in the development and commercialization of successful protein based drug products because of the inherent and high aggregation tendency during various manufacturing processes, storage, and administration. Regulatory activities of dopamine and its derivatives toward. This study investigates the use of plantderived pcs for the inhibition of metal induced protein aggregation. Tetrathiomolybdate induces dimerization of the metalbinding. Research paper promotes protein insolubility and aging in c. Moreover, the derivatives are also able to complex metal ions and to inhibit metal. Aggregation, oxidation, hydrolysis use of disposable containers. There is accumulating evidence that certain metals influence the aggregation propensity. Metal ions and redox balance regulate distinct amyloidlike. A prochelator activated by hydrogen peroxide prevents metal.
Introduction many filamentous biopolymers such as dna and protein filaments are highly charged polyelectrolytes that frequently occur in compact and ordered forms in biological. 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. Thus, the products of the reactions of cisplatin with wln4, both in the absence or presence of tm, were analyzed. Arsenite induced protein aggregation correlates with the toxicity of the. 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. In the processes, heavy metals are one of the major environmental pollutants. Qbp, on the other hand, does not interfere with metalinduced a. Industrial processes can result in airborne contamination such as fine dust, and water and soil contamination.
Aggregation induced electrochemiluminescence by metal binding protein responsive hydrogel scaffolds hui jiang, zhaojian qin, youkun zheng, liu liu, and xuemei wang dr. Platinationinduced unfolding of mbds can lead to protein aggregation. Pathogenic mechanisms of heavy metal inducedalzheimers. 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. Metaltriggered structural transformations, aggregation. In this work, we report a study on bovine serum albumin coldgelation induced by copper or zinc ions. Temperatureinduced unfolding, aggregation, and interaction. A catecholamine neurotransmitter, dopamine da, is suggested to be linked to the pathology of dementia. Pdf heavy metals and metalloids as a cause for protein. Unusual cyclodextrin derivatives as a new avenue to. Prion protein prp misfolding and oligomerization are key pathogenic events in prion disease.
We have previously demonstrated that nonselfassociating protein building blocks can oligomerize to form discrete supramolecular assemblies under the control of metal coordination. Certain ligands such as metal ions can selectively bind to the native state of proteins. To our best knowledge, this is the first study providing the structural basis of the zincinduced aggregation of an rbp implicated in neurological diseases. 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. Metal ioninduced lateral aggregation of filamentous. Whether metalinduced protein aggregates are sequestered to such sites remains to be investigated. Caution must be taken as the preservatives can induce protein aggregation as not all. Arseniteinduced protein aggregation correlates with the toxicity of the. Aggregation propensities of superoxide dismutase g93. Using traditional metal chelating agents, potential regulation of metalinduced a. 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.
Aggregation of metalnanoparticleinduced fluorescence. Aggregates in monoclonal antibody manufacturing processes. Metalmediated selfassembly of protein superstructures. 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. A prochelator activated by hydrogen peroxide prevents. We show here that secondary interactions salt bridges and hydrogen bonds can be critical in guiding the metalinduced selfassembly of proteins. Heavy metals and metalloids as a cause for protein. These protein aggregates are often correlated with diseases. Metal ioninduced lateral aggregation of filamentous viruses fd and m jay x. Unusual cyclodextrin derivatives as a new avenue to modulate self. 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. 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. Although several agents have been recognized to block metal associated a.
In nature, nearly half of all proteins are metalbinding proteins called metalloproteins. 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. 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. Inhibitory activity of curcumin derivatives towards metal. 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. Structural basis of the zincinduced cytoplasmic aggregation. Metalinduced coldgelation of proteins requires two steps. Interaction of albumin and fibrinogen with stainless steel. 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. 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. Chemistry of the metalinduced protein aggregation can be explained by the derjaginlandauverweyoverbeek dlvo theory of intraparticle. When particle aggregation is solely driven by diffusion, one refers to perikinetic aggregation.
Mechanisms of protein aggregation current pharmaceutical biotechnology, 2009, vol. Synergistic effects of metalinduced aggregation of human serum. Metaltriggered structural transformations, aggregation, and. These results suggest that elevation of some metal ions in the brain induces protein aggregation with.
Suppression of polyglutamineinduced protein aggregation. Removal of protein aggregates from biologic apis is crucial due to their potential to increase immunogenicity. Metal induced aggregation of valine capped gold nanoparticles. Global analysis of protein aggregation in yeast during physiological. The disease is associated with toxic chemicals of industrial origin. The understanding of metal ions induced reversible aggregation based on solution electrostatics may lead to potential applications in molecular biology and medicine. Challenges of protein aggregation during purification. Structure of larger aggregates formed can be different. To overcome this problem, we have herein developed iminodiacetic acidmodified human serum. Jan 14, 2019 platination induced unfolding of mbds can lead to protein aggregation. In the present context, this may include both reversible selfassociation and effectively irreversible 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.
Using an in vivo assay for polyglutamine repeatinduced protein aggregation in living animals, we have determined that ectopic overexpression of both human and c. Manganese promotes the aggregation and prionlike cellto. Protein analysis, metal analysis, and aggregation conditions. Metalinduced aggregation of valine capped gold nanoparticles. Aggregation can be enhanced through shear stress e. The freezing rate as well as the method and control of thawing has been previously reported to in.
To investigate the possible link between metals, protein. Cadmium causes misfolding and aggregation of cytosolic proteins. What are the causes of protein aggregation in biologic formulations. The kinetics of protein aggregation has been extensively investigated. Chelating agents also can be used to prevent metalinduced protein aggregation 62,70. Metal ions are essential for life, playing important roles in the human body. Taken together, these findings suggest that protein aggregation is an inherent part of the aging process and that manipulation of protein aggregation by genetic or pharmacologic means promotes longevity in c. Structural implications for heavy metalinduced reversible assembly and aggregation of a protein. An efficient and rapid approach for colorimetric detection of pb. We should also note that pho cuta has a stable trimeric structure even under conditions of 0. 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. Although several agents have been recognized to block metalassociated a. Protein coldgelation has recently received particular attention for its relevance in bio and food technology. Multimeric proteins with two or more subunits can become dissociated into monomers, and monomers or single peptide chain proteins can degrade into peptide fragments.
The black, lefthand bars of figure 4 show that the presence of qbp does not change the turbidity of solutions containing a. Alzheimers disease is an increasing neurodegenerative disease in the aging population. A hallmark of the disease is aggregation of the protein. Effect of ions on agitation and temperatureinduced aggregation reactions of antibodies.
Jan 04, 2010 here, we monitored the metalinduced aggregation of a. In the fast aggregation regime or dlca regime, the aggregates are more. Structural implications for heavy metalinduced reversible. Tungsteninduced denaturation and aggregation of epoetin alfa. Whether metal induced protein aggregates are sequestered to such sites remains to be investigated. Protein aggregation mechanisms, detection, and control. Biophysical inquiry into protein aggregation and amyloid diseases. Aggregation was induced by bufferexchanging 2 mgml sod samples into pbs with or. We undertook an extensive analytical approach to determine the rootcause of the increased aggregation in the affected batches. Disruption of this delicate balance can expose internal. The results of this study show that pcs inhibit zinc induced. Aggregation of biologically important peptides and proteins. In addition, cuinduced fibrils have been shown to have the same morphology as. Metal ioninduced lateral aggregation of filamentous viruses.
We also demonstrate that misfolded prps serve as seeds for templated. 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. Valentina oliveri dipartimento di scienze chimiche, universita di catania, viale a. How cells deal with heavy metal and metalloid induced protein misfolding and aggregation protein qualitycontrol systems monitor the correct functionality of the proteome and protect cells against the harmful accumulation of protein aggregates during environmental stress conditions, as well as during disease and ageing processes 11, 20. Pathogenic mechanisms of heavy metal inducedalzheimers disease. To overcome this problem, we have herein developed iminodiacetic acidmodified human.