96 results match your criteria Amyloidosis Beta2M Dialysis Related


Investigating the Molecular Basis of the Aggregation Propensity of the Pathological D76N Mutant of Beta-2 Microglobulin: Role of the Denatured State.

Int J Mol Sci 2019 Jan 18;20(2). Epub 2019 Jan 18.

Istituto Pasteur-Fondazione Cenci Bolognetti, Dipartimento di Scienze Biochimiche "A. Rossi Fanelli" and Istituto di Biologia e Patologia Molecolari del CNR, Sapienza Università di Roma, 00185 Rome, Italy.

Beta-2 microglobulin (β2m) is a protein responsible for a pathologic condition, known as dialysis-related amyloidosis (DRA), caused by its aggregation and subsequent amyloid formation. A naturally occurring mutation of β2m, D76N, presents a higher amyloidogenic propensity compared to the wild type counterpart. Since the three-dimensional structure of the protein is essentially unaffected by the mutation, the increased aggregation propensity of D76N has been generally ascribed to its lower thermodynamic stability and increased dynamics. Read More

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http://dx.doi.org/10.3390/ijms20020396DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6359115PMC
January 2019
3 Reads

Conformational Properties Relevant to the Amyloidogenicity of β-Microglobulin Analyzed Using Pressure- and Salt-Dependent Chemical Shift Data.

J Phys Chem B 2019 Jan 15;123(4):836-844. Epub 2019 Jan 15.

Kyoto Prefectural University of Medicine , 465 Kajii-cho , Kamigyo-ku, Kyoto 602-8566 , Japan.

β-Microglobulin (βm) is associated with dialysis-related amyloidosis. In vitro experiments have shown that βm forms amyloid fibrils at acidic pHs in the presence of moderate concentrations of salt. Previous studies suggested that acid-denatured βm has a hydrophobic residual structure, and the exposure of the hydrophobic residues enhances the association with seeds or other βm monomers. Read More

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http://dx.doi.org/10.1021/acs.jpcb.8b11408DOI Listing
January 2019
2 Reads

The structure of a β-microglobulin fibril suggests a molecular basis for its amyloid polymorphism.

Nat Commun 2018 10 30;9(1):4517. Epub 2018 Oct 30.

Astbury Centre for Structural Molecular Biology, School of Molecular & Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, LS2 9JT, UK.

All amyloid fibrils contain a cross-β fold. How this structure differs in fibrils formed from proteins associated with different diseases remains unclear. Here, we combine cryo-EM and MAS-NMR to determine the structure of an amyloid fibril formed in vitro from β-microglobulin (βm), the culprit protein of dialysis-related amyloidosis. Read More

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http://www.nature.com/articles/s41467-018-06761-6
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http://dx.doi.org/10.1038/s41467-018-06761-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6207761PMC
October 2018
9 Reads
10.742 Impact Factor

Tendon thickening in dialysis-related joint arthritis is due to amyloid deposits at the surface of the tendon.

Joint Bone Spine 2019 Mar 19;86(2):233-238. Epub 2018 Sep 19.

Department of rheumatology, hôpital Lariboisière, 75010 Paris, France; University Paris 7, 75013 Paris, France. Electronic address:

Objectives: Beta-2-microglobulin (β2M) dialysis-related amyloidosis (DRA), a disabiliting joint disease, has been initially reported in patients under long-term dialysis. The incidence and prevalence has significantly decreased with the improvement in dialysis techniques. Here, we attempted to clarify the clinical and MRI features to improve the diagnosis. Read More

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http://dx.doi.org/10.1016/j.jbspin.2018.08.005DOI Listing
March 2019
6 Reads

Structural Features of Amyloid Fibrils Formed from the Full-Length and Truncated Forms of Beta-2-Microglobulin Probed by Fluorescent Dye Thioflavin T.

Int J Mol Sci 2018 Sep 14;19(9). Epub 2018 Sep 14.

Laboratory of Structural Dynamics, Stability and Folding of Proteins, Institute of Cytology of the Russian Academy of Science, Tikhoretsky ave. 4, St. Petersburg 194064, Russia.

The persistence of high concentrations of beta-2-microglobulin (β2M) in the blood of patients with acute renal failure leads to the development of the dialysis-related amyloidosis. This disease manifests in the deposition of amyloid fibrils formed from the various forms of β2M in the tissues and biological fluids of patients. In this paper, the amyloid fibrils formed from the full-length β2M (β2m) and its variants that lack the 6 and 10 N-terminal amino acids of the protein polypeptide chain (ΔN6β2m and ΔN10β2m, respectively) were probed by using the fluorescent dye thioflavin T (ThT). Read More

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http://dx.doi.org/10.3390/ijms19092762DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6164334PMC
September 2018
7 Reads

Aggregation-phase diagrams of β-microglobulin reveal temperature and salt effects on competitive formation of amyloids amorphous aggregates.

J Biol Chem 2018 09 3;293(38):14775-14785. Epub 2018 Aug 3.

From the Institute for Protein Research, Osaka University, Osaka 565-0871, Japan,

Several serious diseases are associated with crystal-like amyloid fibrils or glass-like amorphous aggregates of denatured proteins. However, protein aggregation involving both types of aggregates has not yet been elucidated in much detail. Using a protein associated with dialysis-related amyloidosis, β-microglobulin (β2m), we previously demonstrated that amyloid fibrils and amorphous aggregates form competitively depending on salt (NaCl) concentration. Read More

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http://dx.doi.org/10.1074/jbc.RA118.004683DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6153281PMC
September 2018
7 Reads

Hemodialysis-related amyloidosis: Is it still relevant?

Semin Dial 2018 11 12;31(6):612-618. Epub 2018 Jun 12.

Department of Nephrology, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan.

Accumulation of amyloid fibrils from β2-microglobulin (β2M) was first recognized as a characteristic osteoarticular complication in long-term hemodialysis (HD) patients and called "HD-related amyloidosis" (HRA). However, this syndrome can also be observed in end-stage renal diseases (ESRD) patients undergoing peritoneal dialysis, and even in patients with chronic renal failure before the initiation of dialytic therapy, suggesting that HD is not a direct cause but that accumulation of β2M or some β2M-associated molecules in the body is a common pathogenesis. Currently the term "dialysis-related amyloidosis" (DRA) is widely used for β2M-amyloid (Aβ2M) amyloidosis associated with ESRD, although DRA patients consist mostly of those undergoing long-term HD. Read More

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http://dx.doi.org/10.1111/sdi.12720DOI Listing
November 2018
16 Reads

The unresolved problem of beta-2 microglobulin amyloid deposits in the intervertebral discs of long-term dialysis patients.

J Orthop Surg Res 2017 Dec 21;12(1):194. Epub 2017 Dec 21.

Department of Orthopaedic Surgery, Spine Division, Bone and Joint Research Center, Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Taoyuan, Taiwan.

Background: Dialysis-related destructive spondyloarthropathy caused by beta-2 microglobulin (β2M) amyloid deposits in intervertebral discs is a major burden for patients undergoing long-term dialysis. This study aimed to quantify the presence of β2M amyloid deposits in the intervertebral disc tissue of such patients and analyze whether there was a significant correlation between β2M accumulation and the duration of dialysis.

Methods: Two groups of patients who had undergone surgery for degenerative spinal pathologies were selected: the dialysis group (n = 29) with long-term dialysis and the control group (n = 10) with no renal impairment. Read More

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http://dx.doi.org/10.1186/s13018-017-0697-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5740589PMC
December 2017
13 Reads

Assessing the effect of D59P mutation in the DE loop region in amyloid aggregation propensity of β2-microglobulin: A molecular dynamics simulation study.

J Cell Biochem 2018 01 31;119(1):782-792. Epub 2017 Jul 31.

Department of Chemistry, School of Basic and Applied Sciences, Sri Guru Granth Sahib World University, Punjab, India.

Dialysis-related amyloidosis (DRA) is a severe condition characterized by the accumulation of amyloidogenic β2-microglobulin (β2m) protein around skeletal joints and bones. The recent studies highlighted a critical role of the DE loop region for β2m stability and amyloid aggregation propensity. Despite significant efforts, the molecular mechanism of enhanced aggregation due to D59P mutation in the DE loop region remain elusive. Read More

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http://doi.wiley.com/10.1002/jcb.26241
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http://dx.doi.org/10.1002/jcb.26241DOI Listing
January 2018
19 Reads

[LEVEL AND OXIDATION OF BETA 2-MICROGLOBULIN IN HEMODIALYSIS PATIENTS TREATED WITH INTRAVENOUS IRON DURING DIALYSIS WITH HIGH-FLUX COMPARED TO LOW-FLUX DIALYZERS].

Harefuah 2017 May;156(5):289-293

Nephrology Department, Galilee Medical Center, Nahariya, Israel.

Introduction: Serum levels of β2-microglobulin (b2M) are significantly higher in patients with end stage renal failure undergoing hemodialysis (HD) and its accumulation accelerates Dialysis Related Amyloidosis (DRA). In HD patients low-flux dialysis, intravenous (IV) iron (administered for the treatment of anemia) affects ß2M removal during dialysis. IV iron also affects the oxidation of plasma proteins, including b2M. Read More

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May 2017
30 Reads

Small molecule-mediated inhibition of β-2-microglobulin-based amyloid fibril formation.

J Biol Chem 2017 06 3;292(25):10630-10638. Epub 2017 May 3.

From the Department of Chemistry, University of Massachusetts, Amherst, Massachusetts 01003

In dialysis patients, β-2 microglobulin (β2m) can aggregate and eventually form amyloid fibrils in a condition known as dialysis-related amyloidosis, which deleteriously affects joint and bone function. Recently, several small molecules have been identified as potential inhibitors of β2m amyloid formation Here we investigated whether these molecules are more broadly applicable inhibitors of β2m amyloid formation by studying their effect on Cu(II)-induced β2m amyloid formation. Using a variety of biophysical techniques, we also examined their inhibitory mechanisms. Read More

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http://dx.doi.org/10.1074/jbc.M116.774083DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5481568PMC
June 2017
13 Reads

Molecular insights into the inhibitory mechanism of rifamycin SV against β-microglobulin aggregation: A molecular dynamics simulation study.

Int J Biol Macromol 2017 Sep 25;102:1025-1034. Epub 2017 Apr 25.

Department of Chemistry, School of Basic and Applied Sciences, Sri Guru Granth Sahib World University, Fatehgarh Sahib 140406, Punjab, India. Electronic address:

Dialysis-related amyloidosis (DRA) is a severe condition characterized by the accumulation of amyloidogenic β-microglobulin (βm) protein around skeletal joints and bones. The small molecules that modulate βm aggregation have been identified in vitro, however, the underlying inhibitory mechanism remain elusive. In the present study, molecular docking and molecular dynamics (MD) simulations were performed to elucidate the inhibitory mechanism of an antibiotic, rifamycin SV (C) reported for its in vitro anti-aggregation activity against βm. Read More

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http://dx.doi.org/10.1016/j.ijbiomac.2017.04.086DOI Listing
September 2017
12 Reads

Dialysis-related Amyloidosis: Is It Gone or Should It Be?

Semin Dial 2017 05 6;30(3):193-196. Epub 2017 Mar 6.

Department of Nephrology, Cliniques universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium.

The prevalence and severity of dialysis-related amyloidosis (DRA) appear to have decreased significantly over the last two decades, although recent, large-scale epidemiological studies show that DRA continues to occur. Recent experimental findings have documented a direct cellular toxicity of β2microglobulin (β2m) fibrils but the mechanisms of β2m fibrillogenesis remain incompletely understood. Although a high plasma concentration of β2m is still considered as a prerequisite for developing DRA, other factors have been clearly incriminated such as older age at dialysis onset and longer dialysis vintage, or suspected effects such as proinflammatory effects of bioincompatible dialysis techniques. Read More

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http://dx.doi.org/10.1111/sdi.12590DOI Listing
May 2017
39 Reads

Influence of heparin molecular size on the induction of C- terminal unfolding in β2-microglobulin.

Mol Biol Res Commun 2016 Dec;5(4):225-232

Department of Neurology, Graduate School of Medical Sciences, Kumamoto University, Honjo, Kumamoto, Japan.

Dialysis-related amyloidosis (DRA) is characterized by accumulation of amyloid β2- microglobulin (β2m) in the interstitial matrix. Matrix substances such as heparin have reportedly been strongly implicated in the pathogenesis of dialysis-related amyloidosis. In clinical setting of hemodialysis, two types of heparin, i. Read More

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5326486PMC
December 2016
16 Reads

Dialysis-related amyloidosis: challenges and solutions.

Int J Nephrol Renovasc Dis 2016 7;9:319-328. Epub 2016 Dec 7.

Department of Nephrology and Dialysis, Azienda Unità Sanitaria Local (AUSL) Hospital "Guglielmo da Saliceto", Piacenza, Italy.

Amyloidosis refers to the extracellular tissue deposition of fibrils composed of low-molecular-weight subunits of a variety of proteins. These deposits may result in a wide range of clinical manifestations depending upon their type, location, and the amount of deposition. Dialysis-related amyloidosis is a serious complication of long-term dialysis therapy and is characterized by the deposition of amyloid fibrils, principally composed of β2 microglobulins (β2M), in the osteoarticular structures and viscera. Read More

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https://www.dovepress.com/dialysis-related-amyloidosis-chall
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http://dx.doi.org/10.2147/IJNRD.S84784DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5153266PMC
December 2016
16 Reads

Characterization of Salt-Induced Oligomerization of Human β2-Microglobulin at Low pH.

J Phys Chem B 2016 08 8;120(32):7815-23. Epub 2016 Aug 8.

Centre for Protein Science, Design and Engineering, Department of Biological Sciences and ‡Department of Chemical Sciences, Indian Institute of Science Education and Research (IISER) , Mohali, Knowledge City, Sector 81, S.A.S. Nagar, Mohali 140306, Punjab, India.

Misfolding and amyloid aggregation of human β2-microglobulin (β2m) have been linked to dialysis-related amyloidosis. Previous studies have shown that in the presence of different salt concentrations and at pH 2.5, β2m assembles into aggregates with distinct morphologies. Read More

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http://dx.doi.org/10.1021/acs.jpcb.6b05619DOI Listing
August 2016
13 Reads

Stepwise unfolding of human β-microglobulin into a disordered amyloidogenic precursor at low pH.

Eur Biophys J 2017 Jan 25;46(1):65-76. Epub 2016 May 25.

Department of Biological Sciences, Centre for Protein Science, Design and Engineering, Indian Institute of Science Education and Research (IISER), Mohali, Mohali, India.

Amyloid fibril formation by human β-microglobulin (βm) is associated with dialysis-related amyloidosis. In order to understand the mechanism of protein misfolding, it is important to characterize the nature and properties of various intermediates formed during protein unfolding. In this work, we studied the effect of pH change on the unfolding of βm using a range of spectroscopic readouts. Read More

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http://dx.doi.org/10.1007/s00249-016-1138-xDOI Listing
January 2017
10 Reads

Rational design of mutations that change the aggregation rate of a protein while maintaining its native structure and stability.

Sci Rep 2016 05 6;6:25559. Epub 2016 May 6.

Dipartimento di Bioscienze, Università degli Studi di Milano, 20133 Milano, Italy.

A wide range of human diseases is associated with mutations that, destabilizing proteins native state, promote their aggregation. However, the mechanisms leading from folded to aggregated states are still incompletely understood. To investigate these mechanisms, we used a combination of NMR spectroscopy and molecular dynamics simulations to compare the native state dynamics of Beta-2 microglobulin (β2m), whose aggregation is associated with dialysis-related amyloidosis, and its aggregation-resistant mutant W60G. Read More

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http://dx.doi.org/10.1038/srep25559DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4858664PMC
May 2016
25 Reads

A systematic molecular dynamics approach to the structural characterization of amyloid aggregation propensity of β2-microglobulin mutant D76N.

Mol Biosyst 2016 Mar;12(3):850-9

Bioinformatics Division, School of Biosciences and Technology, VIT University, Vellore 632 014, Tamil Nadu, India.

Beta-2 microglobulin (β2m) is an amyloidogenic protein belongs to the immunoglobulin superfamily, responsible for the dialysis-related amyloidosis (DRA). Misfolding of β2m is a prerequisite to the formation of systemic amyloidosis that has an effect on the structure and function of the affected organ. The aim of our present study is to intensively explore the structural characterization of amyloid aggregation propensity of recently identified natural mutation D76N by applying the classical molecular dynamics (MD) approach. Read More

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http://dx.doi.org/10.1039/c5mb00759cDOI Listing
March 2016
7 Reads

Significance of the decreased risk of dialysis-related amyloidosis now proven by results from Japanese nationwide surveys in 1998 and 2010.

Nephrol Dial Transplant 2016 04 22;31(4):595-602. Epub 2015 Jul 22.

Committee of Renal Data Registry, Japanese Society for Dialysis Therapy, Tokyo, Japan.

Background: Although dialysis technology greatly improved in recent years, it remained unclear whether those improvements helped decrease the incidence of dialysis-related amyloidosis (DRA). Accordingly, we retrospectively compared the incidence of first-time carpal tunnel surgery (CTS)-as proxy for DRA onset-in two cohorts of chronic hemodialysis patients, with the second cohort studied after dialysis methods (especially dialyzate quality control) had greatly improved.

Methods: We used the 1998 and 2010 Japan Renal Data Registries to compare crude risk of first-time CTS the following year. Read More

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http://ndt.oxfordjournals.org/content/early/2015/07/22/ndt.g
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http://dx.doi.org/10.1093/ndt/gfv276DOI Listing
April 2016
9 Reads

Supersaturation-limited and Unlimited Phase Transitions Compete to Produce the Pathway Complexity in Amyloid Fibrillation.

J Biol Chem 2015 Jul 10;290(29):18134-45. Epub 2015 Jun 10.

From the Institute for Protein Research, Osaka University, Yamadaoka 3-2, Suita, Osaka 565-0871, Japan,

Although amyloid fibrils and amorphous aggregates are two types of aggregates formed by denatured proteins, their relationship currently remains unclear. We used β2-microglobulin (β2m), a protein responsible for dialysis-related amyloidosis, to clarify the mechanism by which proteins form either amyloid fibrils or amorphous aggregates. When ultrasonication was used to accelerate the spontaneous fibrillation of β2m at pH 2. Read More

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http://www.jbc.org/content/290/29/18134.full.pdf
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http://www.jbc.org/lookup/doi/10.1074/jbc.M115.648139
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http://dx.doi.org/10.1074/jbc.M115.648139DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4505058PMC
July 2015
6 Reads

Wild type beta-2 microglobulin and DE loop mutants display a common fibrillar architecture.

PLoS One 2015 24;10(3):e0122449. Epub 2015 Mar 24.

Dipartimento di Bioscienze, Università di Milano, Via Celoria 26, Milano, Italy.

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. Read More

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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0122449PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4372401PMC
February 2016
8 Reads

Role of β2-microglobulin in uremic patients may be greater than originally suspected.

World J Nephrol 2015 Feb;4(1):98-104

Aysegul Zumrutdal, Nephrology Department, Baskent University Adana Teaching and Research Center, Baskent University Hospital, Yuregir, Adana 01230, Turkey.

The role of beta2-microglobulin (β2M) in dialysis-related amyloidosis as a specific amyloid precursor was defined in the 1980s. Studies in those years were largely related to β2M amyloidosis. In 2005, for what was probably the first time in the available literature, we provided data about the association between β2M and early-onset atherosclerosis in hemodialysis patients without co-morbidities. Read More

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http://dx.doi.org/10.5527/wjn.v4.i1.98DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4317633PMC
February 2015
6 Reads

C-terminal unfolding of an amyloidogenic β2-microglobulin fragment: ΔN6β2-microglobulin.

Amyloid 2015 Mar 19;22(1):54-60. Epub 2014 Dec 19.

Suiyukai Clinic , Kashihara, Nara , Japan .

Objectives: A β2-microglobulin (β2m) fragment that lacks the first six amino acids, i.e., ΔN6β2-microglobulin (ΔN6β2m), is an endogenous, proteolytically derived, amyloidogenic fragment of β2m, the precursor protein in Aβ2M amyloidosis (dialysis-related amyloidosis). Read More

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http://dx.doi.org/10.3109/13506129.2014.994057DOI Listing
March 2015
6 Reads

β2-Microglobulin amyloid fibril-induced membrane disruption is enhanced by endosomal lipids and acidic pH.

PLoS One 2014 6;9(8):e104492. Epub 2014 Aug 6.

Astbury Centre for Structural Molecular Biology and School of Molecular and Cellular Biology, University of Leeds, Leeds, United Kingdom.

Although the molecular mechanisms underlying the pathology of amyloidoses are not well understood, the interaction between amyloid proteins and cell membranes is thought to play a role in several amyloid diseases. Amyloid fibrils of β2-microglobulin (β2m), associated with dialysis-related amyloidosis (DRA), have been shown to cause disruption of anionic lipid bilayers in vitro. However, the effect of lipid composition and the chemical environment in which β2m-lipid interactions occur have not been investigated previously. Read More

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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0104492PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4123989PMC
November 2015
22 Reads
7 Citations
3.234 Impact Factor

Calcium binding to beta-2-microglobulin at physiological pH drives the occurrence of conformational changes which cause the protein to precipitate into amorphous forms that subsequently transform into amyloid aggregates.

PLoS One 2014 22;9(4):e95725. Epub 2014 Apr 22.

Department of Biological Sciences, Indian Institute of Science Education and Research (IISER) Mohali, SAS Nagar, Punjab, India.

Using spectroscopic, calorimetric and microscopic methods, we demonstrate that calcium binds to beta-2-microglobulin (β2m) under physiological conditions of pH and ionic strength, in biological buffers, causing a conformational change associated with the binding of up to four calcium atoms per β2m molecule, with a marked transformation of some random coil structure into beta sheet structure, and culminating in the aggregation of the protein at physiological (serum) concentrations of calcium and β2m. We draw attention to the fact that the sequence of β2m contains several potential calcium-binding motifs of the DXD and DXDXD (or DXEXD) varieties. We establish (a) that the microscopic aggregation seen at physiological concentrations of β2m and calcium turns into actual turbidity and visible precipitation at higher concentrations of protein and β2m, (b) that this initial aggregation/precipitation leads to the formation of amorphous aggregates, (c) that the formation of the amorphous aggregates can be partially reversed through the addition of the divalent ion chelating agent, EDTA, and (d) that upon incubation for a few weeks, the amorphous aggregates appear to support the formation of amyloid aggregates that bind to the dye, thioflavin T (ThT), resulting in increase in the dye's fluorescence. Read More

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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0095725PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3995793PMC
January 2015
23 Reads

Insights into the role of the beta-2 microglobulin D-strand in amyloid propensity revealed by mass spectrometry.

Mol Biosyst 2014 Mar 12;10(3):412-20. Epub 2013 Dec 12.

Astbury Centre for Structural Molecular Biology and School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, LS2 9JT, UK.

In vivo beta-2 microglobulin (β2m) forms amyloid fibrils that are associated with the disease dialysis-related amyloidosis. Here, electrospray ionisation-ion mobility spectrometry-mass spectrometry has been used to compare the oligomers formed from wild-type β2m with those formed from a variant of the protein containing a single point mutation in the D strand, H51A, during in vitro fibril assembly. Using the amyloid-binding fluorescent dye, Thioflavin T, to monitor fibrillation kinetics, H51A was shown to exhibit a two-fold increase in the lag-time of fibril formation. Read More

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http://dx.doi.org/10.1039/c3mb70420cDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4006425PMC
March 2014
9 Reads

Dynamics and dimension of an amyloidogenic disordered state of human β(2)-microglobulin.

Eur Biophys J 2013 Oct 24;42(10):767-76. Epub 2013 Aug 24.

Department of Biological Sciences, Indian Institute of Science Education and Research (IISER), Mohali, Knowledge City, Sector 81, S.A.S. Nagar, Mohali, 140306, India.

Human β2-microglobulin (β2m) aggregation is implicated in dialysis-related amyloidosis. Previously, it has been shown that β2m adopts an ensemble of partially unfolded states at low pH. Here we provide detailed structural and dynamical insights into the acid unfolded and yet compact state of β2m at pH 2. Read More

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http://link.springer.com/content/pdf/10.1007%2Fs00249-013-09
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http://link.springer.com/10.1007/s00249-013-0923-z
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http://dx.doi.org/10.1007/s00249-013-0923-zDOI Listing
October 2013
16 Reads

Structure of an early native-like intermediate of β2-microglobulin amyloidogenesis.

Protein Sci 2013 Oct 20;22(10):1349-57. Epub 2013 Aug 20.

Structural Biology Research Centre, VIB, Pleinlaan 2, 1050, Brussel, Belgium; Structural Biology Brussels, Vrije Universiteit Brussel, Pleinlaan 2, 1050, Brussel, Belgium.

To investigate early intermediates of β2-microglobulin (β2m) amyloidogenesis, we solved the structure of β2m containing the amyloidogenic Pro32Gly mutation by X-ray crystallography. One nanobody (Nb24) that efficiently blocks fibril elongation was used as a chaperone to co-crystallize the Pro32Gly β2m monomer under physiological conditions. The complex of P32G β2m with Nb24 reveals a trans peptide bond at position 32 of this amyloidogenic variant, whereas Pro32 adopts the cis conformation in the wild-type monomer, indicating that the cis to trans isomerization at Pro32 plays a critical role in the early onset of β2m amyloid formation. Read More

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http://dx.doi.org/10.1002/pro.2321DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3795493PMC
October 2013
23 Reads

IR spectroscopic analyses of amyloid fibril formation of β2-microglobulin using a simplified procedure for its in vitro generation at neutral pH.

Biophys Chem 2013 Sep 7;179:35-46. Epub 2013 May 7.

Robert Koch-Institut, ZBS 6, Nordufer 20, D-13353 Berlin, Germany.

β2-microglobulin (β2m) is known to be the major component of fibrillar deposits in the joints of patients suffering from dialysis-related amyloidosis. We have developed a simplified procedure to convert monomeric recombinant β2m into amyloid fibrils at physiological pH by a combination of stirring and heating, enabling us to follow conformational changes associated with the assembly by infrared spectroscopy and electron microscopy. Our studies reveal that fibrillogenesis begins with the formation of relatively large aggregates, with secondary structure not significantly altered by the stirring-induced association. Read More

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http://dx.doi.org/10.1016/j.bpc.2013.05.001DOI Listing
September 2013
14 Reads

Distinguishing crystal-like amyloid fibrils and glass-like amorphous aggregates from their kinetics of formation.

Proc Natl Acad Sci U S A 2012 Sep 20;109(36):14446-51. Epub 2012 Aug 20.

Institute for Protein Research, Osaka University, 3-2 Yamadaoka, Suita, Osaka 565-0871, Japan.

Amyloid fibrils and amorphous aggregates are two types of aberrant aggregates associated with protein misfolding diseases. Although they differ in morphology, the two forms are often treated indiscriminately. β(2)-microglobulin (β2m), a protein responsible for dialysis-related amyloidosis, forms amyloid fibrils or amorphous aggregates depending on the NaCl concentration at pH 2. Read More

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http://www.pnas.org/cgi/doi/10.1073/pnas.1208228109
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http://dx.doi.org/10.1073/pnas.1208228109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3437889PMC
September 2012
23 Reads

Advanced glycation end products and β(2)-microglobulin as predictors of carpal tunnel syndrome in hemodialysis patients.

Blood Purif 2012 13;34(1):3-9. Epub 2012 Jun 13.

Department of Internal Medicine III, Jena University Hospital - Friedrich Schiller University, Jena, Germany.

Background/aims: Carpal tunnel syndrome (CTS) is a common clinical presentation of dialysis-related amyloidosis. It was determined whether β(2)-microglobulin (β2M) and advanced glycation end products in serum are predictors of CTS in dialysis patients.

Methods: A total of 385 hemodialysis patients were screened for CTS. Read More

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http://dx.doi.org/10.1159/000338923DOI Listing
June 2013
19 Reads

The monomer-seed interaction mechanism in the formation of the β2-microglobulin amyloid fibril clarified by solution NMR techniques.

J Mol Biol 2012 Sep 6;422(3):390-402. Epub 2012 Jun 6.

Institute for Protein Research, Osaka University, 3-2 Yamadaoka, Suita, Osaka 565-0871, Japan.

Amyloid fibrils are proteinous aggregates associated with various diseases, including Alzheimer's disease, type II diabetes, and dialysis-related amyloidosis. It is generally thought that, during the progression of these diseases, a precursor peptide or protein assumes a partially denatured structure, which interacts with the fibril seed to change into the final amyloid form. β2-Microglobulin (β2m), associated with dialysis-related amyloidosis, is known to form amyloid fibrils at low pH via a partially structured state. Read More

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http://linkinghub.elsevier.com/retrieve/pii/S002228361200432
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http://dx.doi.org/10.1016/j.jmb.2012.05.034DOI Listing
September 2012
27 Reads

Structure, stability, and aggregation of β-2 microglobulin mutants: insights from a Fourier transform infrared study in solution and in the crystalline state.

Biophys J 2012 Apr 3;102(7):1676-84. Epub 2012 Apr 3.

Department of Biotechnology and Biosciences, University of Milano-Bicocca, Milan, Italy.

β-2 microglobulin (β2m) is an amyloidogenic protein involved in dialysis-related amyloidosis. We report here the study of the structural properties of the protein in solution and in the form of single crystals by Fourier transform infrared (FTIR) spectroscopy and microspectroscopy. The investigation has been extended to four β2m mutants previously characterized by x-ray crystallography: Asp(53)Pro, Asp(59)Pro, Trp(60)Gly, and Trp(60)Val. Read More

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http://linkinghub.elsevier.com/retrieve/pii/S000634951200277
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http://dx.doi.org/10.1016/j.bpj.2012.02.045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3318121PMC
April 2012
15 Reads

A recurrent D-strand association interface is observed in β-2 microglobulin oligomers.

FEBS J 2012 Mar 23;279(6):1131-43. Epub 2012 Feb 23.

Dipartimento di Scienze Biomolecolari e Biotecnologie and CIMAINA, Università di Milano, Italy.

β-2 microglobulin (β2m) is an amyloidogenic protein responsible for dialysis-related amyloidosis in man. In the early stages of amyloid fibril formation, β2m associates into dimers and higher oligomers, although the structural details of such aggregates are poorly understood. To characterize the protein-protein interactions supporting the formation of oligomers, three individual β2m cysteine mutants and their disulfide-linked homodimers (DIMC20, DIMC50 and DIMC60) were prepared. Read More

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http://dx.doi.org/10.1111/j.1742-4658.2012.08510.xDOI Listing
March 2012
6 Reads

Characterization of β2-microglobulin conformational intermediates associated to different fibrillation conditions.

J Mass Spectrom 2011 Aug;46(8):734-41

Department of Biotechnology and Biosciences, University of Milano-Bicocca, Piazza della Scienza 2, 20133-Milan, Italy.

β2-Microglobulin (β2m) is the light chain of the class-I major histocompatibility complex, being also the causing agent of dialysis-related amyloidosis, which results from its accumulation as amyloid material in the skeletal joints. This study describes conformational properties of β2m under two distinct, in vitro amyloidogenic conditions: neutral pH in the presence of 20% 2,2,2-trifluoroethanol (TFE) and acidic pH in the absence of TFE. Species distribution analysis by electrospray ionization-mass spectrometry (ESI-MS) is combined with information obtained by ion mobility-mass spectrometry (IM-MS), fluorescence and circular dichroism (CD) spectroscopy. Read More

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http://dx.doi.org/10.1002/jms.1946DOI Listing
August 2011
6 Reads

Structural insights into the pre-amyloid tetramer of β-2-microglobulin from covalent labeling and mass spectrometry.

Biochemistry 2011 Aug 8;50(31):6711-22. Epub 2011 Jul 8.

Department of Chemistry, University of Massachusetts, Amherst, Massachusetts 01003, USA.

The main pathogenic process underlying dialysis-related amyloidosis 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. Read More

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http://pubs.acs.org/doi/abs/10.1021/bi2004894
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http://dx.doi.org/10.1021/bi2004894DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3149750PMC
August 2011
10 Reads

Reversible heat-induced dissociation of β2-microglobulin amyloid fibrils.

Biochemistry 2011 Apr 24;50(15):3211-20. Epub 2011 Mar 24.

Department of Biochemistry, Institute of Biology, Eötvös Loránd University, Budapest H-1117, Hungary.

Recent progress in the field of amyloid research indicates that the classical view of amyloid fibrils, being irreversibly formed highly stable structures resistant to perturbating conditions and proteolytic digestion, is getting more complex. We studied the thermal stability and heat-induced depolymerization of amyloid fibrils of β(2)-microglobulin (β2m), a protein responsible for dialysis-related amyloidosis. We found that freshly polymerized β2m fibrils at 0. Read More

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http://dx.doi.org/10.1021/bi2000017DOI Listing
April 2011
15 Reads

Removal of intact β2-microglobulin at neutral ph by using seed-conjugated polymer beads prepared with β2-microglobulin-derived peptide (58-67).

Biotechnol Prog 2011 Mar-Apr;27(2):521-9. Epub 2011 Mar 1.

School of Chemical and Biological Engineering, Seoul National University, Seoul 151-744, Korea.

Removal of β2-microglobulin (β2M) from the blood of patients suffering from kidney dysfunction is crucial to protect those individuals from getting the diseased state of dialysis-related amyloidosis. By harnessing the nucleation-dependent fibrillation process of amyloidogenesis, a β2M removal strategy has been proposed by preparing seed-conjugated polymer beads and assimilating soluble β2M to the fibrils on the surface at neutral pH. A novel peptide segment of β2M ranging from residue 58 to residue 67 (Lys-Asp-Trp-Ser-Phe-Tyr-Leu-Leu-Tyr-Tyr), which was capable of being fibrillated at neutral pH was isolated. Read More

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http://dx.doi.org/10.1002/btpr.562DOI Listing
September 2011
6 Reads

Intermolecular alignment in β2-microglobulin amyloid fibrils.

J Am Chem Soc 2010 Dec 15;132(48):17077-9. Epub 2010 Nov 15.

Department of Chemistry and Francis Bitter Magnet Laboratory, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.

The deposition of amyloid-like fibrils, composed primarily of the 99-residue protein β2-microglobulin (β2m), is one of the characteristic symptoms of dialysis-related amyloidosis. Fibrils formed in vitro at low pH and low salt concentration share many properties with the disease related fibrils and have been extensively studied by a number of biochemical and biophysical methods. These fibrils contain a significant β-sheet core and have a complex cryoEM electron density profile. Read More

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http://pubs.acs.org/doi/abs/10.1021/ja107987f
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http://dx.doi.org/10.1021/ja107987fDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2996106PMC
December 2010
6 Reads

Glycosaminoglycans enhance the fibrillation propensity of the β2-microglobulin cleavage variant--ΔK58-β2m.

Biochem Biophys Res Commun 2010 Nov 19;402(2):247-51. Epub 2010 Oct 19.

Department of Clinical Biochemistry, Statens Serum Institut, Artillerivej 5, DK-2300 Copenhagen, Denmark.

Dialysis related amyloidosis (DRA) is a serious complication to long-term hemodialysis treatment which causes clinical symptoms such as carpal tunnel syndrome and destructive arthropathies. The disease is characterized by the assembly and deposition of β2-microglobulin (β2m) predominantly in the musculoskeletal system, but the initiating events leading to β2m amyloidogenesis and the molecular mechanisms underlying amyloid fibril formation are still unclear. Glycosaminoglycans (GAGs) and metal ions have been shown to be related to the onset of protein aggregation and to promote de novo fiber formation. Read More

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http://dx.doi.org/10.1016/j.bbrc.2010.10.008DOI Listing
November 2010
7 Reads

DE-loop mutations affect beta2 microglobulin stability, oligomerization, and the low-pH unfolded form.

Protein Sci 2010 Jul;19(7):1386-94

Department of Biotechnology and Biosciences, University of Milano-Bicocca, 20126 Milan, Italy.

Beta2 microglobulin (beta2m) is the light chain of class-I major histocompatibility complex (MHC-I). Its accumulation in the blood of patients affected by kidney failure leads to amyloid deposition around skeletal joints and bones, a severe condition known as Dialysis Related Amyloidosis (DRA). In an effort to dissect the structural determinants of beta2m aggregation, several beta2m mutants have been previously studied. Read More

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http://dx.doi.org/10.1002/pro.419DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2974830PMC
July 2010
9 Reads

Mouse model to study human A beta2M amyloidosis: generation of a transgenic mouse with excessive expression of human beta2-microglobulin.

Amyloid 2010 Jun;17(2):50-62

Department of Aging Biology, Institute on Aging and Adaptation, Shinshu University Graduate School of Medicine, Matsumoto 390-8621, Japan.

Patients on long-term hemodialysis can develop dialysis-related amyloidosis (DRA) due to deposition of beta(2)-microglobulin (beta(2)m) into amyloid fibrils (Abeta(2)M). Despite intensive biochemical studies, the pathogenesis of amyloid deposition in DRA patients remains poorly understood. To elucidate the mechanisms that underlie Abeta(2)M fibril formation in DRA, we generated transgenic mice that overexpress human beta(2)m protein in a mouse beta(2)m gene knockout background (hB2MTg(+/+) mB2m(+/+)). Read More

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http://dx.doi.org/10.3109/13506129.2010.483116DOI Listing
June 2010
11 Reads

Fibrillar vs crystalline full-length beta-2-microglobulin studied by high-resolution solid-state NMR spectroscopy.

J Am Chem Soc 2010 Apr;132(16):5556-7

Centre de RMN à Très Hauts Champs, Université de Lyon (CNRS/ENS Lyon/UCB Lyon 1), 69100 Villeurbanne, France.

Elucidating the fine structure of amyloid fibrils as well as understanding their processes of nucleation and growth remains a difficult yet essential challenge, directly linked to our current poor insight into protein misfolding and aggregation diseases. Here we consider beta-2-microglobulin (beta2m), the MHC-1 light chain component responsible for dialysis-related amyloidosis, which can give rise to amyloid fibrils in vitro under various experimental conditions, including low and neutral pH. We have used solid-state NMR to probe the structural features of fibrils formed by full-length beta2m (99 residues) at pH 2. Read More

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http://pubs.acs.org/doi/abs/10.1021/ja1002839
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http://dx.doi.org/10.1021/ja1002839DOI Listing
April 2010
12 Reads

Native-unlike long-lived intermediates along the folding pathway of the amyloidogenic protein beta2-microglobulin revealed by real-time two-dimensional NMR.

J Biol Chem 2010 Feb 22;285(8):5827-35. Epub 2009 Dec 22.

Department of Biomedical Science and Technology, University of Udine, Piazzale Kolbe 4, 33100 Udine, Italy.

Beta2-microglobulin (beta2m), the light chain of class I major histocompatibility complex, is responsible for the dialysis-related amyloidosis and, in patients undergoing long term dialysis, the full-length and chemically unmodified beta2m converts into amyloid fibrils. The protein, belonging to the immunoglobulin superfamily, in common to other members of this family, experiences during its folding a long-lived intermediate associated to the trans-to-cis isomerization of Pro-32 that has been addressed as the precursor of the amyloid fibril formation. In this respect, previous studies on the W60G beta2m mutant, showing that the lack of Trp-60 prevents fibril formation in mild aggregating condition, prompted us to reinvestigate the refolding kinetics of wild type and W60G beta2m at atomic resolution by real-time NMR. Read More

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http://dx.doi.org/10.1074/jbc.M109.061168DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2820808PMC
February 2010
16 Reads

Seed-conjugated polymer bead for beta2-microglobulin removal at neutral pH.

J Microbiol Biotechnol 2009 Sep;19(9):960-5

School of Chemical and Biological Engineering, Seoul National University, Seoul 151-744, Korea.

beta2-Microglobulin (beta2m) is known to be a major factor for dialysis-related amyloidosis. We have studied beta2m removal through an aggregation process, which was initiated by a ligand that could catch the beta2m monomer and promote its aggregation into fibril. As a ligand, we have prepared beta2m fibril fragments and used them as a seed. Read More

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September 2009
5 Reads

Structural modeling and biochemical studies reveal insights into the molecular basis of the recognition of beta-2-microglobulin by antibody BBM.1.

J Mol Recognit 2009 Nov-Dec;22(6):465-73

State Key Laboratory of Molecular Biology and Research Center for Structural Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, 320 Yue-Yang Road, Shanghai 200031, China.

Human beta-2-microglobulin (beta2m) is the light chain of human leucocyte antigen-I (HLA-I). It can disassociate from HLA-I and accumulate to cause serious dialysis-related amyloidosis (DRA) in long-term hemodialysis patients. Monoclonal antibody (mAb) BBM. Read More

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http://dx.doi.org/10.1002/jmr.964DOI Listing
February 2010
7 Reads

Mechanism of lysophosphatidic acid-induced amyloid fibril formation of beta(2)-microglobulin in vitro under physiological conditions.

Biochemistry 2009 Jun;48(24):5689-99

Department of Biochemistry, Institute of Biology, Eötvös Loránd University, Budapest, H-1117 Hungary.

Beta(2)-microglobulin- (beta2m-) based fibril deposition is the key symptom in dialysis-related amyloidosis. beta2m readily forms amyloid fibrils in vitro at pH 2.5. Read More

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http://dx.doi.org/10.1021/bi900356rDOI Listing
June 2009
13 Reads

Metal binding sheds light on mechanisms of amyloid assembly.

Prion 2009 Jan-Mar;3(1):1-4. Epub 2009 Jan 28.

Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520-8114, USA.

Beta-2 microglobulin (beta2m) is the protein responsible for amyloid deposition in Dialysis-Related Amyloidosis (DRA). Aggregation can be induced by various solution conditions including exposure to divalent metal, incubation at acidic pH, and limited proteolysis. Using Cu(2+) as a trigger, we have trapped, isolated, and crystallized a stable oligomer of beta2m that is populated under amyloidogenic solution conditions (Calabrese et al. Read More

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2676736PMC
June 2009
6 Reads

Human beta-2 microglobulin W60V mutant structure: Implications for stability and amyloid aggregation.

Biochem Biophys Res Commun 2009 Mar 25;380(3):543-7. Epub 2009 Jan 25.

Department of Biomolecular Sciences and Biotechnology, CNR-INFM and CIMAINA, University of Milano, Via Celoria 26, 20133-Milano, Italy.

Beta-2 microglobulin (?2m) is the light chain of class I major histocompatibility complex (MHC-I). Beta2m is an intrinsically amyloidogenic protein that can assemble into amyloid fibrils in a concentration dependent manner. Beta2m is accumulated in serum of haemodialysed patients, and deposited in the skeletal joints, causing dialysis related amyloidosis. Read More

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http://dx.doi.org/10.1016/j.bbrc.2009.01.116DOI Listing
March 2009
51 Reads