Affinity Binding of Glycosaminoglycans with β&lt;sub&gt;2&lt;/sub&gt;-Microglobulin

Ohashi, Kenichi; Kisilevsky, Robert; Yanagishita, Masaki

doi:10.1159/000049037

Cited by 36 publications

(24 citation statements)

References 25 publications

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“…The ability of heparin to stabilize and favor the formation of oligomers, even though the affinity measured between heparin and monomeric ␤ 2 -m is very low (32), suggests that oligomeric species might be the preferential target of heparin. 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.…”

Section: Discussionmentioning

confidence: 99%

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

111

104

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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: Discussionmentioning

confidence: 99%

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

111

104

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“…For example, b 2 M without associated MHC class 1 heavy chains can be deposited in the connective tissue as amyloid in chronic renal disease (Monti et al 2005, Myers et al 2006. Intact and partially cleaved forms of b 2 M can bind to connective tissue matrix components including collagen and glycosaminoglycans (Ohashi et al 2002, Yamaguchi et al 2003 in a manner that involves conformational changes induced by low pH (Monti et al 2005) or copper ions (Villanueva et al 2004, Deng et al 2006. Limited proteolysis to the DN6-b 2 M form of human b 2 M alters binding in amyloid but is not required (Monti et al 2005).…”

Section: Discussionmentioning

confidence: 99%

Changes in major proteins in the embryonic capsule during immobilization (fixation) of the conceptus in the third week of pregnancy in the mare

Quinn

Hayes²,

Waelchli³

et al. 2007

Reproduction

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During the third week of pregnancy, the equine conceptus is enclosed within a capsule, the glycan composition of which changes at around day 16 (ovulationZday 0) when the conceptus becomes immobilized (fixed) in the uterine lumen. Our objective was to characterize the process of fixation by identifying changes in major capsule-associated proteins. Individual equine conceptuses (nZ55) were collected transcervically by uterine lavage between days 13.5 and 26.5. Major proteins extracted from capsules were compared with those in fluids from the uterus and yolk sac by SDS-PAGE. Until day 14, a major capsule-associated protein that migrated at w10 kDa was identified by N-terminal sequencing as equine b2 microglobulin (b2M). During fixation, b2M in the capsule underwent limited proteolysis to an w8 kDa form lacking nine amino acids from the N terminus, and was subsequently degraded. Expression of b2M mRNA was detected in the yolk-sac wall tissues and endometrium between days 13.5 and 17.5. During this period, b2M in the capsule was evidently not part of a complex with major histocompatibility complex class 1 heavy a chain bands because these were undetectable in the capsule and uterine lavage. Uterocalin (p19) was detected in uterine lavage and capsule throughout fixation, but in yolk-sac fluid only before fixation. These studies indicate that intact b2M is a major protein associated with the embryonic capsule before fixation, after which it undergoes limited proteolysis to a truncated w8 kDa form that remains in the capsule after the conceptus is immobilized.

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“…A few molecules are known to bind the native form of b 2 -m, namely Congo Red [13][14][15], 8-anilino-1-naphthalene sulfonic acid [14], heparin [15][16][17], and the drug suramin [11], although none of these compounds has so far been demonstrated to stabilize the native form of b 2 -m.…”

Section: Introductionmentioning

confidence: 99%

Search of ligands for the amyloidogenic protein β2-microglobulin by capillary electrophoresis and other techniques

et al. 2005

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Beta2-microglobulin (beta2-m) is a small amyloidogenic protein normally present on the surface of most nucleated cells and responsible for dialysis-related amyloidosis, which represents a severe complication of long-term hemodialysis. A therapeutic approach for this amyloidosis could be based on the stabilization of beta2-m through the binding to a small molecule, and consequent inhibition of protein misfolding and amyloid fibril formation. A few compounds have been described to weakly bind beta2-m, including the drug suramin. The lack of a binding site for nonpolypeptidic ligands on the beta2-m structure makes it difficult for both the identification of functional groups responsible for the binding and the search of hits to be optimized. The characterization of the binding properties of suramin for beta2-m by using three different techniques (surface plasmon resonance, affinity CE (ACE), ultrafiltration) is here described and the results obtained are compared. The common features of the chemical structures of the compounds known to bind the protein led us to select 200 sulfonated/suramin-like molecules from a wider chemical library on the basis of similarity rules, so as to possibly single out some interesting hits and to gain more information on the functional groups involved in the binding. The development of screening methods to test the compounds by using ultrafiltration and ACE is described.

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Affinity Binding of Glycosaminoglycans with β<sub>2</sub>-Microglobulin

Cited by 36 publications

References 25 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

Changes in major proteins in the embryonic capsule during immobilization (fixation) of the conceptus in the third week of pregnancy in the mare

Search of ligands for the amyloidogenic protein β2-microglobulin by capillary electrophoresis and other techniques

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