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Malaguarnera, Mariano; Restuccia, Salvatore; Fazio, Ignazio Di; Zoccolo, Anna Maria; Trovato, Barbara Adriana; Pistone, Giovanni

doi:10.1023/a:1018855928753

Cited by 19 publications

(7 citation statements)

References 20 publications

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“…A number of studies have suggested that β-2m may be a useful marker in the development of hepatitis (Rashid et al 1981;Nagafuchi and Scheuer 1986;Yegane et al 2004). The measurement of β-2m levels in a number of hepatic diseases revealed that significantly elevated levels are found in the serum of patients with alcoholic and biliary cirrhosis, chronic hepatitis C, and metastatic liver cancer (Rashid et al 1981;Malaguarnera et al 1997). …”

Section: Discussionmentioning

confidence: 99%

Proteomic investigation of urinary markers of carbon-tetrachloride-induced hepatic fibrosis in the Hanover Wistar rat

et al. 2008

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Proteomic techniques such as two-dimensional gel electrophoresis (2-DGE) and mass spectrometry have become important tools for the identification of novel biomarkers of toxicity and disease. Ideally, such biomarkers need to be sensitive and organ specific, but, recently, it has become apparent that it would be an additional benefit to be able to measure biomarkers in samples obtained using non-invasive methods. The present study is concerned with the identification of novel urinary markers of hepatic fibrosis. In a carbon-tetrachloride-induced liver fibrosis rat model, analysis of urine by 2-DGE revealed an increase in the concentration of a number of proteins in animals with hepatic fibrosis. Using in-gel trypsin digest and nano-scale liquid chromatography combined with electrospray ionisation tandem mass spectrometry, protein spots were identified as copper/zinc superoxide dismutase, D: -dopachrome tautomerase, beta-2-microglobulin and neutrophil gelatinase associated lipocalin. These proteins are known to have important roles in the inflammatory response.

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Section: Discussionmentioning

confidence: 99%

Proteomic investigation of urinary markers of carbon-tetrachloride-induced hepatic fibrosis in the Hanover Wistar rat

et al. 2008

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“…2 The circulating concentration of β2m in DRA patients increases up to ∼60 times above the normal level of 0.1 μM, but elevated β2m concentrations alone are not sufficient to trigger fibrillogenesis. 3,4 β2m amyloid formation must therefore result from other factors related to hemodialysis, but the exact mechanism in vivo is not known. In vitro , β2m oligomerization and fibril formation can be generated several ways, including by incubation of the protein under acidic conditions, 5 by truncation of the first six N-terminal amino acids, 6 by mixing the protein with collagen at pH 6.4, 7 by sonication of the protein with sodium dodecyl sulfate at pH 7.0, 8 and by incubation of the protein under physiological conditions in the presence of stoichiometric amounts of Cu(II).…”

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confidence: 99%

Unique Effect of Cu(II) in the Metal-Induced Amyloid Formation of β-2-Microglobulin

et al. 2014

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β-2-Microglobulin (β2m) forms amyloid fibrils in the joints of patients undergoing hemodialysis treatment as a result of kidney failure. In the presence of stoichiometric amounts of Cu(II), β2m self-associates into discrete oligomeric species, including dimers, tetramers, and hexamers, before ultimately forming amyloid fibrils that contain no copper. To improve our understanding of whether Cu(II) is unique in its ability to induce β2m amyloid formation and to delineate the coordinative interactions that allow Cu(II) to exert its effect, we have examined the binding of Ni(II) and Zn(II) to β2m and the resulting influence that these metals have on β2m aggregation. We find that, in contrast to Cu(II), Ni(II) does not induce the oligomerization or aggregation of β2m, while Zn(II) promotes oligomerization but not amyloid fibril formation. Using X-ray absorption spectroscopy and new mass spectrometry-related techniques, we find that different binding modes are responsible for the different effects of Ni(II) and Zn(II). By comparing the binding modes of Cu(II) with Ni(II), we find that Cu(II) binding to Asp59 and the backbone amide between the first two residues of β2m are important for allowing the formation of amyloid-competent oligomers, as Ni(II) appears not to bind these sites on the protein. The oligomers formed in the presence of Zn(II) are permitted by this metal’s ability to bridge two β2m units via His51. These oligomers, however, are not able to progress to form amyloid fibrils because Zn(II) does not induce the required structural changes near the N-terminus and His31.

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“…Upon renal failure, serum levels of β2m increase up to ~60 times above their normal levels of about 0.1 µM, and the protein aggregates into insoluble amyloid deposits (3,4). An elevated level of β2m, however, is not unique to renal failure patients and is not sufficient to trigger fibrillogenesis (5,6). β2m amyloid formation must therefore result from factors particular to hemodialysis.…”

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confidence: 99%

Structural Insights into the Pre-Amyloid Tetramer of β-2-Microglobulin from Covalent Labeling and Mass Spectrometry

et al. 2011

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The main pathogenic process underlying dialysis-related amyloidosis (DRA) is the accumulation of β-2-microglobulin (β2m) as amyloid fibrils in the musculoskeletal system, and some evidence suggests that Cu(II) may play a role in β2m amyloid formation. Cu(II)-induced β2m fibril formation is preceded by the formation of discrete, oligomeric intermediates, including dimers, tetramers, and hexamers. In this work, we use selective covalent labeling reactions combined with mass spectrometry to investigate the amino acids responsible for mediating tetramer formation in wild-type β2m. By comparing the labeling patterns of the monomer, dimer, and tetramer, we find evidence that the tetramer interface is formed by the interaction of D strands from one dimer unit and G strands from another dimer unit. This covalent labeling data along with molecular dynamics calculations enable the construction of a tetramer model that indicates how the protein might proceed to form even higher order oligomers.

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Cited by 19 publications

References 20 publications

Proteomic investigation of urinary markers of carbon-tetrachloride-induced hepatic fibrosis in the Hanover Wistar rat

Proteomic investigation of urinary markers of carbon-tetrachloride-induced hepatic fibrosis in the Hanover Wistar rat

Unique Effect of Cu(II) in the Metal-Induced Amyloid Formation of β-2-Microglobulin

Structural Insights into the Pre-Amyloid Tetramer of β-2-Microglobulin from Covalent Labeling and Mass Spectrometry

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