Beta-2-Microglobulin-Associated Amyloidosis

Floege, Jürgen; Ehlerding, G.

doi:10.1159/000188801

Cited by 129 publications

(111 citation statements)

References 118 publications

(165 reference statements)

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“…Dialysis Related Amyloidosis (DRA) is a pathological state afflicting patients suffering from kidney failure treated by long-term hemodialysis, related to inefficient b2m catabolism. 2,3 Under such pathological conditions the concentration of circulating b2m increases by a factor of 10-50, 2,4 leading to b2m…”

Section: Introductionmentioning

confidence: 99%

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DE‐loop mutations affect β2 microglobulin stability, oligomerization, and the low‐pH unfolded form

et al. 2010

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b2 microglobulin (b2m) 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 b2m aggregation, several b2m mutants have been previously studied. Among these, three single-residue mutations in the loop connecting strands D and E (W60G, W60V, D59P) have been shown to affect b2m amyloidogenic properties, and are here considered. To investigate the biochemical and biophysical properties of wild-type (w.t.) b2m and the three mutants, we explored thermal unfolding by Trp fluorescence and circular dichroism (CD). The W60G mutant reveals a pronounced increase in conformational stability. Protein oligomerization and reduction kinetics were investigated by electrospray-ionization mass spectrometry (ESI-MS). All the mutations analyzed here reduce the protein propensity to form soluble oligomers, suggesting a role for the DE-loop in intermolecular interactions. A partially folded intermediate, which may be involved in protein aggregation induced by acids, accumulates for all the tested proteins at pH 2.5 under oxidizing conditions. Moreover, the kinetics of disulfide reduction reveals specific differences among the tested mutants. Thus, b2m DE-loop mutations display long-range effects, affecting stability and structural properties of the native protein and its low-pH intermediate. The evidence presented here hints to a crucial role played by the DE-loop in determining the overall properties of native and partially folded b2m.

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Section: Introductionmentioning

confidence: 99%

“…In vivo, b2m normally circulates at $0.1 lM concentration. 2 However, b2m is soluble and stable in vitro at mM concentrations 6,7 and can be reversibly unfolded. 8,9 Several conditions that enable in vitro b2m amyloid formation have been found.…”

Section: Introductionmentioning

confidence: 99%

DE‐loop mutations affect β2 microglobulin stability, oligomerization, and the low‐pH unfolded form

et al. 2010

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“…In patients suffering from endstage renal disease who are treated with hemodialysis therapy, β2m levels rise and amyloid plaques develop throughout the joints and connective tissue. 2 Although an elevated serum level of β2m may be necessary for aggregation, it is not sufficient as β2m remains stably folded at > 1 mM concentration at 37 °C. 3,4 Furthermore, it can be reversibly folded in vitro [5][6][7] and amyloid is not reported in other diseases with elevated levels in serum.…”

Section: Introductionmentioning

confidence: 99%

Metal binding sheds light on mechanisms of amyloid assembly

Calabrese

Miranker

2009

Prion

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β-2 microglobulin (β2m) 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 β2m that is populated under amyloidogenic solution conditions (Calabrese et al. Nat Struct Mol Biol 2008; 15:965-71). This structure reveals that Cu 2+ -binding is associated with dramatic conformational rearrangements. This has allowed us to postulate a set of structural changes common to all β2m aggregation pathways. Cu 2+ serves as a potential trigger in other aggregation systems such as Aβ, α-synuclein, and mammalian Prion (PrP). A comparison of Cu 2+ binding to β2m and PrP reveals common features. Therefore, in addition to providing insight into DRA, induction of structure by Cu 2+ binding appears to be a recurring structural motif for pathological changes in conformation. Backgroundβ2m is the 99 residue, 12 kDa non-covalent light chain of the Class I Major Histocompatibility Complex (MHC). Its function is to ensure proper folding and cell-surface expression of the MHC. 1 In the course of normal turnover, β2m is released to the serum and catabolized by the kidneys. In patients suffering from endstage renal disease who are treated with hemodialysis therapy, β2m levels rise and amyloid plaques develop throughout the joints and connective tissue. 2 Although an elevated serum level of β2m may be necessary for aggregation, it is not sufficient as β2m remains stably folded at > 1 mM concentration at 37 °C. 3,4 Furthermore, it can be reversibly folded in vitro 5-7 and amyloid is not reported in other diseases with elevated levels in serum. 8,9 Therefore, aggregation must be triggered by features unique to hemodialysis therapy.As β2m exists as a stable monomer under near physiological conditions, 3,10 much effort has been focused on understanding the molecular mechanism by which self association is triggered. Many approaches have been used to induce β2m aggregation. These include limited proteolysis, 11 incubation at acidic pH, 12 and exposure to detergents or organic solvents. 13,14 In 2001, we discovered that β2m is a Cu 2+ -binding protein. 4 Whereas β2m apo is not amyloidogenic, β2m holo is aggregation-prone. Cu 2+ Mediated OligomerizationWe are interested in Cu 2+ -dependent aggregation of β2m for several reasons. First, hemodialysis patients may be exposed to elevated levels of divalent cation as a consequence of therapy. This is apparent in the historical use of Cu 2+ in the preparation of dialysis membranes, and in water quality standards which permit as much as 1.6 μM Cu 2+ in hemodialysate. 15 This is comparable to the ~3 μM affinity of β2m measured in vitro. 4 Second, early experiments revealed that although Cu 2+ is necessary to initiate aggregation, mature fibers remain stable in the presence of a metal chelate. 10 This allowed the possibility that Cu 2+ acti...

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“…1), is one of the many known amyloid diseases. It occurs in all patients undergoing long-term hemodialysis (32,33) and is typified by deposition of amyloid plaques in skeletal tissue (34). ␤ 2 m fibril growth occurs via multiple pathways (35,36), and the fibrils formed through each route have distinct morphology.…”

mentioning

confidence: 99%

Nucleation of protein fibrillation by nanoparticles

Linse

Cabaleiro-Lago

Xue

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

810

769

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Nanoparticles present enormous surface areas and are found to enhance the rate of protein fibrillation by decreasing the lag time for nucleation. Protein fibrillation is involved in many human diseases, including Alzheimer's, Creutzfeld-Jacob disease, and dialysis-related amyloidosis. Fibril formation occurs by nucleationdependent kinetics, wherein formation of a critical nucleus is the key rate-determining step, after which fibrillation proceeds rapidly. We show that nanoparticles (copolymer particles, cerium oxide particles, quantum dots, and carbon nanotubes) enhance the probability of appearance of a critical nucleus for nucleation of protein fibrils from human ␤2-microglobulin. The observed shorter lag (nucleation) phase depends on the amount and nature of particle surface. There is an exchange of protein between solution and nanoparticle surface, and ␤2-microglobulin forms multiple layers on the particle surface, providing a locally increased protein concentration promoting oligomer formation. This and the shortened lag phase suggest a mechanism involving surface-assisted nucleation that may increase the risk for toxic cluster and amyloid formation. It also opens the door to new routes for the controlled self-assembly of proteins and peptides into novel nanomaterials.amyloid ͉ nanotoxicology ͉ surface-assisted nucleation

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Beta-2-Microglobulin-Associated Amyloidosis

Cited by 129 publications

References 118 publications

DE‐loop mutations affect β2 microglobulin stability, oligomerization, and the low‐pH unfolded form

DE‐loop mutations affect β2 microglobulin stability, oligomerization, and the low‐pH unfolded form

Metal binding sheds light on mechanisms of amyloid assembly

Nucleation of protein fibrillation by nanoparticles

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