Structural heterogeneity in the pre-amyloid oligomers of β-2-microglobulin

Publication date: Available online 9 November 2019Source: Journal of Molecular BiologyAuthor(s): Tyler M. Marcinko, Chungwen Liang, Sergey Savinov, Jianhen Chen, Richard W. VachetAbstractIn dialysis patients, the protein β2-microglobulin (β2m) forms amyloid fibrils in a condition known as dialysis-related amyloidosis. To understand the early stages of the amyloid assembly process, we have used native electrospray ionization (ESI) together with ion mobility mass spectrometry (IM-MS) to study soluble pre-amyloid oligomers. ESI-IM-MS reveals the presence of multiple conformers for the dimer, tetramer, and hexamer that precede the Cu(II)-induced amyloid assembly process, results which are distinct from β2m oligomers formed at low pH. Experimental and computational results indicate that the predominant dimer is a Cu(II)-bound structure with an antiparallel side-by-side configuration. In contrast, tetramers exist in solution in both Cu(II)-bound and Cu(II)-free forms. Selective depletion of Cu(II)-bound species results in two primary conformers – one that is compact and another that is more expanded. Molecular modeling and molecular dynamics simulations identify models for these two tetrameric conformers with unique interactions and interfaces that enthalpically compensate for the loss of Cu(II). Unlike with other amyloid systems in which conformational heterogeneity is often associated with different amyloid morphologies or off-pathway events, conformational h...
Source: Journal of Molecular Biology - Category: Molecular Biology Source Type: research

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Publication date: Available online 9 November 2019Source: Journal of Molecular BiologyAuthor(s): Tyler M. Marcinko, Chungwen Liang, Sergey Savinov, Jianhen Chen, Richard W. VachetAbstractIn dialysis patients, the protein β2-microglobulin (β2m) forms amyloid fibrils in a condition known as dialysis-related amyloidosis. To understand the early stages of the amyloid assembly process, we have used native electrospray ionization (ESI) together with ion mobility mass spectrometry (IM-MS) to study soluble preamyloid oligomers. ESI-IM-MS reveals the presence of multiple conformers for the dimer, tetramer, and hexamer tha...
Source: Journal of Molecular Biology - Category: Molecular Biology Source Type: research
Amyloidosis-associated amyloid fibrils are formed by denatured proteins when supersaturation of denatured proteins is broken. β2-Microglobulin (β2m) forms amyloid fibrils and causes dialysis-related amyloidosis in patients receiving long-term hemodialysis. Although amyloid fibrils of β2m in patients are observed at neutral pH, formation of β2m amyloids in vitro has been difficult to discern at neutral pH because of the amyloid-resistant native structure. Here, to further understand the mechanism underlying in vivo amyloid formation, we investigated the relationship between protein folding/unfolding and ...
Source: Journal of Biological Chemistry - Category: Chemistry Authors: Tags: Protein Structure and Folding Source Type: research
Recent advances have led to promising new diagnostic strategies and treatment options for AL amyloidosis.Nephrology Dialysis Transplantation
Source: Medscape Today Headlines - Category: Consumer Health News Tags: Nephrology Journal Article Source Type: news
ConclusionsAccording to our data, NT-proBNP> 7400  pg/ml are associated with the severity of kidney damage and the risk of non-cardiac mortality in ND MM patients.Legal entity responsible for the studyThe authors.FundingHas not received any funding.DisclosureAll authors have declared no conflicts of interest.
Source: Annals of Oncology - Category: Cancer & Oncology Source Type: research
Transient oligomers are commonly formed in the early stages of amyloid assembly. Determining the structure(s) of these species and defining their role(s) in assembly is key to devising new routes to control disease. Here, using a combination of chemical kinetics, NMR spectroscopy and other biophysical methods, we identify and structurally characterize the oligomers required for amyloid assembly of the protein DN6, a truncation variant of human β2-microglobulin (b2m) found in amyloid deposits in the joints of patients with dialysis-related amyloidosis. The results reveal an assembly pathway which is initiated by the fo...
Source: eLife - Category: Biomedical Science Tags: Structural Biology and Molecular Biophysics Source Type: research
Authors: Huang WH, Hu CC, Yen TH, Hsu CW, Weng CH Abstract Introduction: Carpal tunnel syndrome (CTS) is a severe complication observed in long-term maintenance hemodialysis (MHD) patients. The most common cause of CTS is dialysis-related β2-microglobulin amyloidosis, which is associated with inflammation and oxidative stress in dialysis patients. Patients on MHD have higher blood lead levels (BLLs) than the general population. Lead (Pb) exposure in chronic dialysis patients has been noted to induce oxidative stress and inflammation. Therefore, lead-related inflammation and oxidative stress might contribute to...
Source: Renal Failure - Category: Urology & Nephrology Tags: Ren Fail Source Type: research
In conclusion, long dialysis period was a risk factor for DRA.
Source: Journal of Bone and Mineral Metabolism - Category: Orthopaedics Source Type: research
Amyloid deposition of WT human β2-microglobulin (WT-hβ2m) in the joints of long-term hemodialysis patients is the hallmark of dialysis-related amyloidosis. In vitro, WT-hβ2m does not form amyloid fibrils at physiological pH and temperature unless co-solvents or other reagents are added. Therefore, understanding how fibril formation is initiated and maintained in the joint space is important for elucidating WT-hβ2m aggregation and dialysis-related amyloidosis onset. Here, we investigated the roles of collagen I and the commonly administered anticoagulant, low-molecular-weight (LMW) heparin, in the initia...
Source: Journal of Biological Chemistry - Category: Chemistry Authors: Tags: Molecular Bases of Disease Source Type: research
In conclusion, the VHH antibodies were successfully used as affinity ligands in the preparation of novel immunoadsorbents by the site-specific immobilization, and effectively adsorbed β2-m from blood, therefore opening a new avenue for efficient hemodialysis.
Source: Molecules - Category: Chemistry Authors: Tags: Article Source Type: research
Authors: Kuragano T, Kida A, Yahiro M, Nakanishi T Abstract BACKGROUND: With the advancement of technology, a dialysis membrane has been developed to achieve the efficient removal of beta-2 microglobulin (β2MG), which could not be removed with previous hemodialysis (HD) membranes. Recently, there has been an increase in the population of elderly chronic kidney disease (CKD) patients with chronic inflammation and malnutrition. The optimal extracorporeal circulation treatment for elderly CKD patients is not certain. SUMMARY: We have reported the clinical advantages, such as improvements in nutritional, infla...
Source: Contributions to Nephrology - Category: Urology & Nephrology Tags: Contrib Nephrol Source Type: research
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