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Acta Obstetricia Et Gynecologica... 2007An altered renal function is an essential component of the patho-physiology of pre-eclampsia. The plasma levels of low molecular mass proteins, e.g. beta-trace protein,...
BACKGROUND
An altered renal function is an essential component of the patho-physiology of pre-eclampsia. The plasma levels of low molecular mass proteins, e.g. beta-trace protein, beta-2-microglobulin and cystatin C, are increased in the third trimester of normal pregnancy. The plasma levels of cystatin C and beta-2-microglobulin are further increased in pre-eclampsia, and the cystatin C level has been reported to be a reliable marker for the disease. The aim of this investigation was to study the plasma levels of beta-trace protein, beta-2-microglobulin and cystatin C in pre-eclampsia, and to determine the diagnostic performance of these proteins compared to that of urate and creatinine.
METHODS
A case-control study of 57 women diagnosed with pre-eclampsia, and 218 healthy women with uncomplicated singleton pregnancies in the third trimester. Women in the catchment area of Lund, Sweden, were included during an 18-month period from October 2003 to April 2005. Venous blood samples were drawn upon inclusion when diagnosis was made. The maternal plasma concentrations of the 3 proteins were analysed by automated particle-enhanced immunoturbidimetric assays.
RESULTS
The plasma levels of the 3 proteins were significantly higher in the third trimester of pre-eclamptic patients compared to healthy pregnant women in the third trimester. The upper reference limits (parametric 97.5 percentile) were 2.57 mg/l for beta-2-microglobulin, 0.72 mg/l for beta-trace protein and 1.37 mg/l for cystatin C. ROC analysis showed similar diagnostic performance for the 3 proteins, with beta-trace protein displaying the best diagnostic performance of all the analytes.
CONCLUSIONS
In this study, the maternal plasma levels of beta2-microglobulin, beta-trace protein and cystatin C were all significantly elevated in pre-eclampsia compared to those of healthy pregnant women, and displayed similar diagnostic performance for diagnosing pre-eclampsia. The results indicate that low molecular mass proteins are useful as markers of renal impairment in pre-eclampsia.
Topics: Adult; Biomarkers; Blood Proteins; Case-Control Studies; Cystatin C; Cystatins; Female; Humans; Intramolecular Oxidoreductases; Lipocalins; Pre-Eclampsia; Predictive Value of Tests; Pregnancy; Pregnancy Trimester, Third; ROC Curve; beta 2-Microglobulin
PubMed: 17653875
DOI: 10.1080/00016340701318133 -
Blood Oct 1999Major histocompatibility complex (MHC) molecules play an important role in antigen presentation for induction of tumor as well as cellular and humoral immunities. Recent... (Comparative Study)
Comparative Study
Major histocompatibility complex (MHC) molecules play an important role in antigen presentation for induction of tumor as well as cellular and humoral immunities. Recent studies using anti-MHC antibodies demonstrated that antibodies specific for HLA class I molecules induced cellular activation and a type of apoptosis that may be distinct from Fas-dependent or TNFR (tumor necrosis factor-alpha receptor)-dependent processes. We purified a previously untested apoptosis-inducing factor from HL-60 human leukemic cell-conditioned media to homogeneity and sequenced it. It was identified as beta(2)-microglobulin (beta(2)m), which has been previously known as thymotaxin and is a part of the HLA class I antigen complex. beta(2)m acts on both T-leukemic cells and myeloid leukemic cells to induce apoptosis, which then activates caspase 1 and 3. Cross-linking studies showed that biotinilated beta(2)m recognized an epitope distinct from those recognized by the anti-HLA class I antibody, as reported previously. We demonstrated that beta(2)m plays a previously unrecognized and important role in regulating the elimination of tumor cells, which occurs as a result of the action of beta(2)m as an apoptosis-inducing factor.
Topics: Amino Acid Chloromethyl Ketones; Amino Acid Sequence; Animals; Antibodies, Monoclonal; Apoptosis; Culture Media, Conditioned; Cysteine Proteinase Inhibitors; Fas Ligand Protein; HL-60 Cells; Humans; K562 Cells; Membrane Glycoproteins; Mice; Molecular Sequence Data; Neoplasm Proteins; Oligopeptides; Receptors, Tumor Necrosis Factor; Sequence Alignment; Sequence Homology, Amino Acid; Tumor Cells, Cultured; Tumor Necrosis Factor-alpha; U937 Cells; beta 2-Microglobulin; fas Receptor
PubMed: 10515878
DOI: No ID Found -
The FEBS Journal Jul 2011Proteins hosting main β-sheets adopt specific strategies to avoid intermolecular interactions leading to aggregation and amyloid deposition. Human beta-2 microglobulin...
Proteins hosting main β-sheets adopt specific strategies to avoid intermolecular interactions leading to aggregation and amyloid deposition. Human beta-2 microglobulin (β2m) displays a typical immunoglobulin fold and is known to be amyloidogenic in vivo. Upon severe kidney deficiency, β2m accumulates in the bloodstream, triggering, over the years, pathological deposition of large amyloid aggregates in joints and bones. A β-bulge observed on the edge D β-strand of some β2m crystal structures has been suggested to be crucial in protecting the protein from amyloid aggregation. Conversely, a straight D-strand, observed in different crystal structures of monomeric β2m, could promote amyloid aggregation. More recently, the different conformations observed for the β2m D-strand have been interpreted as the result of intrinsic flexibility, rather than being assigned to a functional protective role against aggregation. To shed light on such contrasting picture, the mutation Asp53→Pro was engineered in β2m, aiming to impair the formation of a regular/straight D-strand. Such a mutant was characterized structurally and biophysically by CD, X-ray crystallography and MS, in addition to an assessment of its amyloid aggregation trends in vitro. The results reported in the present study highlight the conformational plasticity of the edge D-strand, and show that even perturbing the D-strand structure through a Pro residue has only marginal effects on protecting β2m from amyloid aggregation in vitro.
Topics: Amino Acid Sequence; Amyloid; Circular Dichroism; Crystallography, X-Ray; Humans; Models, Molecular; Molecular Sequence Data; Mutation; Protein Folding; Protein Structure, Secondary; Spectrometry, Mass, Electrospray Ionization; beta 2-Microglobulin
PubMed: 21569201
DOI: 10.1111/j.1742-4658.2011.08157.x -
Scientific Reports Sep 2015β-2-microglobulin (β2m) self-aggregates to form amyloid fibril in renal patients taking long-term dialysis treatment. Despite the extensive structural and mutation...
β-2-microglobulin (β2m) self-aggregates to form amyloid fibril in renal patients taking long-term dialysis treatment. Despite the extensive structural and mutation studies carried out so far, the molecular details on the factors that dictate amyloidogenic potential of β2m remain elusive. Here we report molecular dynamics simulations followed by the solvation thermodynamic analyses on the wild-type β2m and D76N, D59P, and W60C mutants at the native (N) and so-called aggregation-prone intermediate (IT) states, which are distinguished by the native cis- and non-native trans-Pro32 backbone conformations. Three major structural and thermodynamic characteristics of the IT-state relative to the N-state in β2m protein are detected that contribute to the increased amyloidogenic potential: (i) the disruption of the edge D-strand, (ii) the increased solvent-exposed hydrophobic interface, and (iii) the increased solvation free energy (less affinity toward solvent water). Mutation effects on these three factors are shown to exhibit a good correlation with the experimentally observed distinct amyloidogenic propensity of the D76N (+), D59P (+), and W60C (-) mutants (+/- for enhanced/decreased). Our analyses thus identify the structural and thermodynamic characteristics of the amyloidogenic intermediates, which will serve to uncover molecular mechanisms and driving forces in β2m amyloid fibril formation.
Topics: Amyloidogenic Proteins; Humans; Hydrophobic and Hydrophilic Interactions; Molecular Dynamics Simulation; Mutation; Protein Conformation; Protein Stability; Solvents; Thermodynamics; beta 2-Microglobulin
PubMed: 26348154
DOI: 10.1038/srep13631 -
The Journal of Biological Chemistry Apr 2015β2-Microglobulin is responsible for systemic amyloidosis affecting patients undergoing long-term hemodialysis. Its genetic variant D76N causes a very rare form of... (Review)
Review
β2-Microglobulin is responsible for systemic amyloidosis affecting patients undergoing long-term hemodialysis. Its genetic variant D76N causes a very rare form of familial systemic amyloidosis. These two types of amyloidoses differ significantly in terms of the tissue localization of deposits and for major pathological features. Considering how the amyloidogenesis of the β2-microglobulin mechanism has been scrutinized in depth for the last three decades, the comparative analysis of molecular and pathological properties of wild type β2-microglobulin and of the D76N variant offers a unique opportunity to critically reconsider the current understanding of the relation between the protein's structural properties and its pathologic behavior.
Topics: Amyloid; Amyloidosis; Doxycycline; Humans; Models, Molecular; Mutation; Protein Aggregation, Pathological; Protein Conformation; Renal Dialysis; Single-Chain Antibodies; beta 2-Microglobulin
PubMed: 25750126
DOI: 10.1074/jbc.R115.639799 -
Proceedings of the National Academy of... Aug 1979beta2-Microglobulin has been synthesized in vitro by using a rabbit reticulocyte lysate system and mRNA from the mouse tumor cell line EL4. The molecule is synthesized...
beta2-Microglobulin has been synthesized in vitro by using a rabbit reticulocyte lysate system and mRNA from the mouse tumor cell line EL4. The molecule is synthesized as a precursor with an NH2-terminal extension of 19 amino acids: Ser-X-Ser-Val-X-Leu-Val-Phe-Leu-Val-Leu-Val-Ser-Leu-X-Gly-Leu-Tyr-X. The processing and segregation of this peripheral membrane protein are directly comparable to those of secretory proteins and integral membrane proteins: addition of dog pancreas microsomal membranes during translation caused conversion to the processed chain, but addition of membranes after synthesis did not; only the processed chain sedimented with the membrane vesicles and was protected from proteolysis by the vesicles; and processing of nascent beta 2-microglobulin was blocked by competitive inhibitors that prevent processing and segregation of secretory and integral membrane proteins. These results suggest that the signal sequences of secretory proteins, integral membrane proteins, and peripheral membrane proteins have a common function and a common receptor on the cytoplasmic face of dog pancreas microsomal membranes. This system also provides a means for studying in vitro the expression and function of the major histocompatibility antigens that are associated with beta 2-microglobulin on cell surfaces.
Topics: Amino Acid Sequence; Animals; Beta-Globulins; Binding Sites; Cell Line; Cell-Free System; Membrane Proteins; Mice; Microsomes; Protein Biosynthesis; Protein Precursors; Reticulocytes; beta 2-Microglobulin
PubMed: 91168
DOI: 10.1073/pnas.76.8.3651 -
Protein Science : a Publication of the... May 2017Amyloid fibrils are fibrillar deposits of denatured proteins associated with amyloidosis and are formed by a nucleation and growth mechanism. We revisited an alternative...
Amyloid fibrils are fibrillar deposits of denatured proteins associated with amyloidosis and are formed by a nucleation and growth mechanism. We revisited an alternative and classical view of amyloid fibrillation: amyloid fibrils are crystal-like precipitates of denatured proteins formed above solubility upon breaking supersaturation. Various additives accelerate and then inhibit amyloid fibrillation in a concentration-dependent manner, suggesting that the combined effects of stabilizing and destabilizing forces affect fibrillation. Heparin, a glycosaminoglycan and anticoagulant, is an accelerator of fibrillation for various amyloidogenic proteins. By using β -microglobulin, a protein responsible for dialysis-related amyloidosis, we herein examined the effects of various concentrations of heparin on fibrillation at pH 2. In contrast to previous studies that focused on accelerating effects, higher concentrations of heparin inhibited fibrillation, and this was accompanied by amorphous aggregation. The two-step effects of acceleration and inhibition were similar to those observed for various salts. The results indicate that the anion effects caused by sulfate groups are one of the dominant factors influencing heparin-dependent fibrillation, although the exact structures of fibrils and amorphous aggregates might differ between those formed by simple salts and matrix-forming heparin. We propose that a conformational phase diagram, accommodating crystal-like amyloid fibrils and glass-like amorphous aggregates, is important for understanding the effects of various additives.
Topics: Amyloid; Amyloidosis; Heparin; Hydrogen-Ion Concentration; Models, Chemical; Protein Structure, Quaternary; Renal Dialysis; beta 2-Microglobulin
PubMed: 28249361
DOI: 10.1002/pro.3149 -
Annals of the Rheumatic Diseases Apr 1981The levels of beta 2-microglobulin (beta 2-m) in serum and urine of 24 seropositive patients with rheumatoid arthritis (RA) treated with regular gold (sodium...
The levels of beta 2-microglobulin (beta 2-m) in serum and urine of 24 seropositive patients with rheumatoid arthritis (RA) treated with regular gold (sodium aurothiomalate) injections have been investigated. The values obtained were compared with levels from 20 seropositive patients with RA treated only with nonsteroidal anti-inflammatory drugs and 20 age and sex matched normal controls who had received no medication. A significant increase of urinary beta 2-m levels was found in the gold-treated RA group. No correlation between dose of gold received and the levels of beta 2-m in the urine could be established. There was also no correlation between the erythrocyte sedimentation rate (ESR) or total lymphocyte count and beta 2-m levels in serum or urine. We conclude that serum and urinary beta 2-m levels appear to be poor indices of joint inflammation, but sequential urinary beta 2-m levels may prove valuable in monitoring the development of renal tubular lesions due to gold therapy.
Topics: Adult; Aged; Arthritis, Rheumatoid; Beta-Globulins; Female; Gold Sodium Thiomalate; Humans; Male; Middle Aged; beta 2-Microglobulin
PubMed: 6164344
DOI: 10.1136/ard.40.2.157 -
Molecules (Basel, Switzerland) Jul 2022The supersaturation of a solution refers to a non-equilibrium phase in which the solution is trapped in a soluble state, even though the solute's concentration is... (Review)
Review
The supersaturation of a solution refers to a non-equilibrium phase in which the solution is trapped in a soluble state, even though the solute's concentration is greater than its thermodynamic solubility. Upon breaking supersaturation, crystals form and the concentration of the solute decreases to its thermodynamic solubility. Soon after the discovery of the prion phenomena, it was recognized that prion disease transmission and propagation share some similarities with the process of crystallization. Subsequent studies exploring the structural and functional association between amyloid fibrils and amyloidoses solidified this paradigm. However, recent studies have not necessarily focused on supersaturation, possibly because of marked advancements in structural studies clarifying the atomic structures of amyloid fibrils. On the other hand, there is increasing evidence that supersaturation plays a critical role in the formation of amyloid fibrils and the onset of amyloidosis. Here, we review the recent evidence that supersaturation plays a role in linking unfolding/folding and amyloid fibril formation. We also introduce the HANABI (HANdai Amyloid Burst Inducer) system, which enables high-throughput analysis of amyloid fibril formation by the ultrasonication-triggered breakdown of supersaturation. In addition to structural studies, studies based on solubility and supersaturation are essential both to developing a comprehensive understanding of amyloid fibrils and their roles in amyloidosis, and to developing therapeutic strategies.
Topics: Amyloid; Amyloidosis; Humans; Solutions; Thermodynamics; beta 2-Microglobulin
PubMed: 35889461
DOI: 10.3390/molecules27144588 -
PloS One 2015Beta-2 microglobulin (β2m) is the protein responsible for a pathologic condition known as dialysis related amyloidosis. In recent years an important role has been...
Beta-2 microglobulin (β2m) is the protein responsible for a pathologic condition known as dialysis related amyloidosis. In recent years an important role has been assigned to the peptide loop linking strands D and E (DE loop) in determining β2m stability and amyloid propensity. Several mutants of the DE loop have been studied, showing a good correlation between DE loop geometrical strain, protein stability and aggregation propensity. However, it remains unclear whether the aggregates formed by wild type (wt) β2m and by the DE loop variants are of the same kind, or whether the mutations open new aggregation pathways. In order to address this question, fibrillar samples of wt and mutated β2m variants have been analysed by means of atomic force microscopy and infrared spectroscopy. The data here reported indicate that the DE loop mutants form aggregates with morphology and structural organisation very similar to the wt protein. Therefore, the main effect of β2m DE loop mutations is proposed to stem from the different stabilities of the native fold. Considerations on the structural role of the DE loop in the free monomeric β2m and as part of the Major Histocompatibility Complex are also presented.
Topics: Amyloid; Amyloidosis; Humans; Microscopy, Atomic Force; Models, Molecular; Mutation; Protein Aggregation, Pathological; Protein Stability; Renal Dialysis; Spectrophotometry, Infrared; beta 2-Microglobulin
PubMed: 25803608
DOI: 10.1371/journal.pone.0122449