Unfolding, Aggregation, and Seeded Amyloid Formation of Lysine-58-Cleaved β<sub>2</sub>-Microglobulin

Heegaard, Niels H. H.; Jørgensen, Thomas J. D.; Rozlosnik, Noémi; Corlin, Dorthe B.; Pedersen, Jens Oluf; Tempesta, Anna Gabriella; Roepstorff, Peter; Bauer, Rogert; Nissen, Mogens Holst

doi:10.1021/bi047594t

Cited by 58 publications

(88 citation statements)

References 54 publications

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“…Indeed, diseaserelated amyloid deposits in tissues usually consist of peptide fragments derived from larger protein precursors in vivo, such as amyloid-protein, gelsolin, British amyloid peptide, and others. 40,41) Other examples, including lysine-58-cleaved 2 -microglobulin [42][43][44] and N-terminally truncated 2 -microglobulin, 45,46) also elevate fibril propensity by increasing the local flexibility of the polypeptide chain.…”

Section: Implications For Amyloid Fibril Formationmentioning

confidence: 99%

Systematic Analysis of Aggregates from 38 Kinds of Non Disease-Related Proteins: Identifying the Intrinsic Propensity of Polypeptides to Form Amyloid Fibrils

Aso

Shiraki

Takagi

2007

Bioscience, Biotechnology, and Biochemistry

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Section: Implications For Amyloid Fibril Formationmentioning

confidence: 99%

Systematic Analysis of Aggregates from 38 Kinds of Non Disease-Related Proteins: Identifying the Intrinsic Propensity of Polypeptides to Form Amyloid Fibrils

Aso

Shiraki

Takagi

2007

Bioscience, Biotechnology, and Biochemistry

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“…Furthermore, at neutral pH, ␤ 2 -m can elongate preformed fibrils when the solution contains trifluoroethanol (6) or sodium dodecyl sulfate (7) or when the protein populates an intermediate state of the folding pathway (8). The ability of ␤ 2 -m to elongate preformed fibrils at neutral pH is also enhanced by truncation at the N terminus (9) as well as by cleavage of the peptide bond at the carbonyl side of Lys-58 (10).…”

mentioning

confidence: 99%

Collagen Plays an Active Role in the Aggregation of β2-Microglobulin under Physiopathological Conditions of Dialysis-related Amyloidosis

Relini

Canale

Stefano

et al. 2006

Journal of Biological Chemistry

138

135

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Dialysis-related amyloidosis is characterized by the deposition of insoluble fibrils of ␤ 2 -microglobulin (␤ 2 -m) in the musculoskeletal system. Atomic force microscopy inspection of ex vivo amyloid material reveals the presence of bundles of fibrils often associated to collagen fibrils. Aggregation experiments were undertaken in vitro with the aim of reproducing the physiopathological fibrillation process. To this purpose, atomic force microscopy, fluorescence techniques, and NMR were employed. We found that in temperature and pH conditions similar to those occurring in periarticular tissues in the presence of flogistic processes, ␤ 2 -m fibrillogenesis takes place in the presence of fibrillar collagen, whereas no fibrils are obtained without collagen. Moreover, the morphology of ␤ 2 -m fibrils obtained in vitro in the presence of collagen is extremely similar to that observed in the ex vivo sample. This result indicates that collagen plays a crucial role in ␤ 2 -m amyloid deposition under physiopathological conditions and suggests an explanation for the strict specificity of dialysis-related amyloidosis for the tissues of the skeletal system. We hypothesize that positively charged regions along the collagen fiber could play a direct role in ␤ 2 -m fibrillogenesis. This hypothesis is sustained by aggregation experiments performed by replacing collagen with a poly-L-lysine-coated mica surface. As shown by NMR measurements, no similar process occurs when poly-L-lysine is dissolved in solution with ␤ 2 -m. Overall, the findings are consistent with the estimates resulting from a simplified collagen model whereby electrostatic effects can lead to high local concentrations of oppositely charged species, such as ␤ 2 -m, that decay on moving away from the fiber surface.The deposition of ␤ 2 -microglobulin (␤ 2 -m) 2 into amyloid fibrils is the hallmark of dialysis-related amyloidosis (DRA), a disease arising as a complication of long-term hemodialysis. ␤ 2 -m is a 99-residue protein (molecular mass 11.7 kDa) that represents the light chain of the major histocompatibility complex class I (MHCI), an integral membrane protein involved in the immune response. As a result of normal MHCI catabolism, ␤ 2 -m is released in the serum from the cell surface and carried to the kidney for clearance. In the presence of kidney failure, the concentration of free circulating ␤ 2 -m can increase by up to 50-fold; the persistent increase in ␤ 2 -m concentration results in amyloid deposition, preferentially localized in the musculoskeletal system. The accumulation of ␤ 2 -m deposits has been shown to cause arthralgias, destructive osteoarthropathies, and carpal tunnel syndrome (1). Although a high concentration of ␤ 2 -m is a necessary condition for the onset of the disease, there is not a strict correlation between the disease severity and ␤ 2 -m levels (2), suggesting that other factors might be involved in ␤ 2 -m amyloid deposition.The aggregation process of ␤ 2 -m has been the object of extensive investigation for many years. Severa...

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“…Interestingly, although macrophages are found in association with amyloid deposits in patients suffering from DRA, and macrophages and macrophage-like cells cultured in vitro have been shown to promote the aggregation of a variety of amyloidogenic precursors into amyloid-like fibrils (13-16), the role of these cell types in DRA remains poorly understood (17,18). Importantly in this regard, ␤ 2 m fibrils have been found within the lysosomes of macrophages associated with amyloid in patients suffering from DRA (19), raising the intriguing possibility that these organelles could play a role in the amyloidogenesis of ␤ 2 m either by the acidic pH, therein promoting the self-assembly of ␤ 2 m into amyloid fibrils (20 -24), or by proteolytic cleavage, producing fragments with increased amyloid propensity (8,9,25). Alternatively, the macrophages associated with ␤ 2 m amyloid deposits may play a protective role in DRA by capturing extracellular amyloid by phagocytosis for degradation (26).…”

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confidence: 99%

“…Because intact wild-type ␤ 2 m is unable to form amyloidlike fibrils at neutral pH in vitro in the absence of pre-formed seeds, a role for amyloid-associated factors (6,7), limited proteolysis (8,9), or interaction with collagen (10) or glycosaminoglycans (11,12) have all been implicated in the initiation of amyloid deposition in vivo. Interestingly, although macrophages are found in association with amyloid deposits in patients suffering from DRA, and macrophages and macrophage-like cells cultured in vitro have been shown to promote the aggregation of a variety of amyloidogenic precursors into amyloid-like fibrils (13)(14)(15)(16), the role of these cell types in DRA remains poorly understood (17,18).…”

mentioning

confidence: 99%

Investigation into the Role of Macrophages in the Formation and Degradation of β2-Microglobulin Amyloid Fibrils

Morten¹,

Gosal²,

Radford

et al. 2007

Journal of Biological Chemistry

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Dialysis related amyloidosis is a serious complication of longterm hemodialysis in which ␤ 2 -microglobulin (␤ 2 m) forms amyloid fibrils that deposit predominantly in cartilaginous tissues. How these fibrils form in vivo, however, is poorly understood. Here we perform a systematic investigation into the role of macrophages in the formation and degradation of ␤ 2 m amyloid fibrils, building on observations that macrophages are found in association with ␤ 2 m amyloid deposits in vivo and that these cells contain intra-lysosomal ␤ 2 m amyloid. In live cell imaging experiments we demonstrate that macrophages internalize monomeric ␤ 2 m, whereupon it is sorted to lysosomes. At lysosomal pH ␤ 2 m self-associates in vitro to form amyloid-like fibrils with an array of morphologies as visualized by atomic force microscopy. Cleavage of the monomeric protein by both macrophages and lysosomal proteases isolated from these cells results in the rapid degradation of the monomeric protein, preventing amyloid formation. Incubation of macrophages with preformed fibrils revealed that macrophages internalize amyloid-like fibrils formed extracellularly, but in marked contrast with the monomeric protein, the fibrils were not degraded within macrophage lysosomes. Correspondingly ␤ 2 m fibrils were highly resistant to degradation by high concentrations of lysosomal proteases isolated from macrophages. Despite their enormous degradative capacity, therefore, macrophage lysosomes cannot ameliorate dialysis-related amyloidosis by degrading pre-existing amyloid fibrils, but lysosomal proteases may play a protective role by eliminating amyloid precursors before ␤ 2 m fibrils can accumulate in what may represent an otherwise fibrillogenic environment.The amyloidoses are a class of conformational diseases associated with the aggregation of proteins or peptides into insoluble amyloid fibrils (1). More than 20 proteins and peptides are currently known to form amyloid deposits that are associated with human disease (1). One such protein is ␤ 2 -microglobulin (␤ 2 m), 4 the precursor of amyloid fibrils formed in dialysis-related amyloidosis (DRA), a debilitating complication of longterm hemodialysis (2-4). ␤ 2 m forms the non-covalently bound light chain of the major histocompatibility class I complex, which is expressed on the plasma membrane of all nucleated cells (5). Cells continually shed ␤ 2 m from their surface, whereupon the protein is normally removed from the serum by degradation in the proximal tubule of the kidney (3). In patients with end stage renal disease, however, neither the kidney nor the dialysis membrane can remove ␤ 2 m from the circulation, resulting in a 10 -50-fold increase in the concentration of ␤ 2 m in the serum (2-4). The sustained high concentration of ␤ 2 m therein appears to be one key initiating factor in the aggregation of this protein into insoluble amyloid fibrils, which typically accumulate in the musculoskeletal system resulting in bone and joint destruction (2-4).How amyloid fibrils form from ␤ 2 m in vivo ...

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Unfolding, Aggregation, and Seeded Amyloid Formation of Lysine-58-Cleaved β₂-Microglobulin

Cited by 58 publications

References 54 publications

Systematic Analysis of Aggregates from 38 Kinds of Non Disease-Related Proteins: Identifying the Intrinsic Propensity of Polypeptides to Form Amyloid Fibrils

Systematic Analysis of Aggregates from 38 Kinds of Non Disease-Related Proteins: Identifying the Intrinsic Propensity of Polypeptides to Form Amyloid Fibrils

Collagen Plays an Active Role in the Aggregation of β2-Microglobulin under Physiopathological Conditions of Dialysis-related Amyloidosis

Investigation into the Role of Macrophages in the Formation and Degradation of β2-Microglobulin Amyloid Fibrils

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Unfolding, Aggregation, and Seeded Amyloid Formation of Lysine-58-Cleaved β2-Microglobulin

Cited by 58 publications

References 54 publications

Systematic Analysis of Aggregates from 38 Kinds of Non Disease-Related Proteins: Identifying the Intrinsic Propensity of Polypeptides to Form Amyloid Fibrils

Systematic Analysis of Aggregates from 38 Kinds of Non Disease-Related Proteins: Identifying the Intrinsic Propensity of Polypeptides to Form Amyloid Fibrils

Collagen Plays an Active Role in the Aggregation of β2-Microglobulin under Physiopathological Conditions of Dialysis-related Amyloidosis

Investigation into the Role of Macrophages in the Formation and Degradation of β2-Microglobulin Amyloid Fibrils

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Unfolding, Aggregation, and Seeded Amyloid Formation of Lysine-58-Cleaved β₂-Microglobulin