The solution structure of human β2‐microglobulin reveals the prodromes of its amyloid transition

Verdone, Giuliana; Corazza, Alessandra; Viglino, Paolo; Pettirossi, Fabio; Giorgetti, Sofia; Mangione, Palma; Andreola, Alessia; Stoppini, Monica; Bellotti, Vittorio; Esposito, Gennaro

doi:10.1110/ps.29002

Cited by 154 publications

(129 citation statements)

References 48 publications

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“…The remarkable differences in the kinetics of oligomerization observed at pH 6.4 or 7.4, in the absence of any significant conformational change in the protein at these two pHs, as observed in the past by NMR (33,34), confirm previous suggestions (35) that His residues might have an important role in the oligomerization and interaction with heparin. In fact, these are the only residues that could change their ionization state between pH 6.4 and 7.4.…”

Section: Discussionsupporting

confidence: 88%

Heparin Strongly Enhances the Formation of β2-Microglobulin Amyloid Fibrils in the Presence of Type I Collagen

Relini

Stefano

Torrassa

et al. 2008

Journal of Biological Chemistry

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The tissue specificity of fibrillar deposition in dialysis-related amyloidosis is most likely associated with the peculiar interaction of ␤ 2 -microglobulin (␤ 2 -m) with collagen fibers. However, other co-factors such as glycosaminoglycans might facilitate amyloid formation. In this study we have investigated the role of heparin in the process of collagen-driven amyloidogenesis. In fact, heparin is a well known positive effector of fibrillogenesis, and the elucidation of its potential effect in this type of amyloidosis is particularly relevant because heparin is regularly given to patients subject to hemodialysis to prevent blood clotting. We have monitored by atomic force microscopy the formation of ␤ 2 -m amyloid fibrils in the presence of collagen fibers, and we have discovered that heparin strongly accelerates amyloid deposition. The mechanism of this effect is still largely unexplained. Using dynamic light scattering, we have found that heparin promotes ␤ 2 -m aggregation in solution at pH 6.4. Morphology and structure of fibrils obtained in the presence of collagen and heparin are highly similar to those of natural fibrils. The fibril surface topology, investigated by limited proteolysis, suggests that the general assembly of amyloid fibrils grown under these conditions and in vitro at low pH is similar. The exposure of these fibrils to trypsin generates a cleavage at the C-terminal of lysine 6 and creates the 7-99 truncated form of ␤ 2 -m (⌬N6␤ 2 -m) that is a ubiquitous constituent of the natural ␤ 2 -m fibrils. The formation of this ␤ 2 -m species, which has a strong propensity to aggregate, might play an important role in the acceleration of local amyloid deposition. Dialysis-related amyloidosis (DRA),2 a severe disease arising as a complication of long term hemodialysis, involves the deposition of ␤ 2 -microglobulin (␤ 2 -m) amyloid fibrils in bones and ligaments. ␤ 2 -m constitutes the light chain of the major histocompatibility complex class I and CD1 (1), and in normal catabolism, it is continuously released in the serum and cleared from the circulation by the kidney. The replacement of renal function by hemodialysis does not efficiently remove ␤ 2 -m. The persistent increase of its plasma concentration is associated with ␤ 2 -m deposition in the osteotendineous system, which is the specific target tissue of this type of amyloidosis. Among extra-cerebral amyloidoses, DRA represents the most striking case of tissue-specific targeting. Although other organs can be involved, bones and ligaments never escape amyloid deposition. Homma (2) first pointed out that collagen might be involved in determining this tissue specificity and demonstrated a collagen/␤ 2 -m interaction.We have recently determined the binding properties governing the collagen/␤ 2 -m interaction, and we found that the latter is quite weak but is enhanced when ␤ 2 -m is truncated at the N-terminal end, and the pH is reduced from 7.4 to 6.4 (3). We subsequently demonstrated that fibrillar collagen (type I), which is abundant in skeletal...

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Section: Discussionsupporting

confidence: 88%

Heparin Strongly Enhances the Formation of β2-Microglobulin Amyloid Fibrils in the Presence of Type I Collagen

Relini

Stefano

Torrassa

et al. 2008

Journal of Biological Chemistry

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104

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“…As already reported (19), the 1 H NMR spectrum of an ordinary solution of R3A␤2m, acquired immediately after dissolution, shows the same pattern as observed with wild-type protein (12), which is consistent with the strong conformational similarities between the two species (19). Data were collected using clear solutions prepared without filtering and, sometimes, with mild centrifugation.…”

Section: Assessment Of the Stability Of R3a␤2m Solutions In The Presesupporting

confidence: 82%

“…In vivo, ␤2m causes amyloidosis via accumulation in the tissues of patients with renal failure as a result of long term hemodialysis (11). The structure of ␤2m and the molecular aspects of its amyloid transition have been extensively investigated in recent years, not only because of the clinical relevance of dialysis-related amyloidosis but also as a model for other amyloidogenic proteins (12)(13)(14)(15)(16)(17)(18)(19).…”

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confidence: 99%

Monitoring the Interaction between β2-Microglobulin and the Molecular Chaperone αB-crystallin by NMR and Mass Spectrometry

Esposito

Garvey

Alverdi

et al. 2013

Journal of Biological Chemistry

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Background: ␤ 2 -Microglobulin (␤2m) is a paradigmatic amyloidogenic protein. Results:In vitro, the molecular chaperone ␣B-crystallin affects the oligomerization and the fibrillogenesis of ␤2m and its R3A mutant. Conclusion: ␣B-crystallin prevents ␤2m aggregation at various stages of its aggregation pathway. Significance: Molecular chaperones may be relevant to amyloid formation in vivo.

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“…Previous studies have implicated His13, His31, and His51 as well as the N-terminus in native-state metal binding. [16][17][18][19] Of the three histidines above, our own studies have shown that only mutation of His31 affects native-state Cu 2+ affinity. 16 Abbreviations: β2m, β-2 microglobulin; PrP, prion; MHC, major histocompatibility complex; DRA, dialysis-related amyloidosis…”

Section: Cu 2+ Mediated Oligomerizationmentioning

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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The solution structure of human β2‐microglobulin reveals the prodromes of its amyloid transition

Cited by 154 publications

References 48 publications

Heparin Strongly Enhances the Formation of β2-Microglobulin Amyloid Fibrils in the Presence of Type I Collagen

Heparin Strongly Enhances the Formation of β2-Microglobulin Amyloid Fibrils in the Presence of Type I Collagen

Monitoring the Interaction between β2-Microglobulin and the Molecular Chaperone αB-crystallin by NMR and Mass Spectrometry

Metal binding sheds light on mechanisms of amyloid assembly

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