Study of Chaperone-Like Activity of Human Haptoglobin: Conformational Changes under Heat Shock Conditions and Localization of Interaction Sites

Ettrich, Rüdiger; Brandt, Wolfgang; Kopecký, Vladimı́r; Baumruk, Vladimı́r; Hofbauerová, Kateřina; Pavlı́ček, Zdeněk

doi:10.1515/bc.2002.187

Cited by 26 publications

(39 citation statements)

References 43 publications

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“…Hp retained the ability to inhibit amyloid formation even when complexed with hemoglobin, although this activity was reduced when compared with that of uncomplexed Hp. This is consistent with a previous report that complexation with Hb reduces but does not abolish the ability of Hp to inhibit the amorphous aggregation of protein (33). We have reported previously that activation of ␣ 2 M by interaction with trypsin abolished its ability to inhibit the amorphous heat-induced aggregation of two globular proteins (11).…”

Section: Discussionsupporting

confidence: 93%

α2-Macroglobulin and Haptoglobin Suppress Amyloid Formation by Interacting with Prefibrillar Protein Species

Yerbury

Kumita

Meehan

et al. 2009

Journal of Biological Chemistry

110

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␣ 2 -Macroglobulin (␣ 2 M) and haptoglobin (Hp) are both abundant secreted glycoproteins that are best known for their protease trapping and hemoglobin binding activities, respectively. Like the small heat shock proteins, both these glycoproteins have in common the ability to protect a range of proteins from stress-induced amorphous aggregation and have been described as extracellular chaperones. Using an array of biophysical techniques, this study establishes that in vitro at substoichiometric levels and under physiological conditions ␣ 2 M and Hp both inhibit the formation of amyloid fibrils from a range of proteins. We also provide evidence that both ␣ 2 M and Hp interact with prefibrillar species to maintain the solubility of amyloidogenic proteins. These findings suggest that both ␣ 2 M and Hp are likely to play an important role in controlling the inappropriate aggregation of proteins in the extracellular environment.

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Section: Discussionsupporting

confidence: 93%

α2-Macroglobulin and Haptoglobin Suppress Amyloid Formation by Interacting with Prefibrillar Protein Species

Yerbury

Kumita

Meehan

et al. 2009

Journal of Biological Chemistry

110

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“…1) associates as a homodimer with an elongated head-to-tail structure involving interactions between the heavy chain of one monomer and the N-terminal light chain of its counterpart. Interestingly, the heavy chain of HPT is homologous to the catalytic domain of serine proteases (40). HPT shows two hydrophobic pockets on the surface of each heavy chain, representing potential chaperone-binding sites (40).…”

Section: Haptoglobin: the Plasma Hemoglobin Trappermentioning

confidence: 99%

“…Interestingly, the heavy chain of HPT is homologous to the catalytic domain of serine proteases (40). HPT shows two hydrophobic pockets on the surface of each heavy chain, representing potential chaperone-binding sites (40). An ab dimer of Hb in a trans configuration binds to each heavy chain, then the HPT:Hb stoichiometry is 1:1 (40).…”

Section: Haptoglobin: the Plasma Hemoglobin Trappermentioning

confidence: 99%

Hemoglobin and heme scavenging

Ascenzi

Bocedi

Visca

et al. 2005

IUBMB Life (International Union of Biochemistry and Molecular B

235

221

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Release of hemoglobin into plasma is a physiological phenomenon associated with intravascular hemolysis. In plasma, stable haptoglobin‐hemoglobin complexes are formed and these are subsequently delivered to the reticulo‐endothelial system by CD163 receptor‐mediated endocytosis. Heme arising from the degradation of hemoglobin, myoglobin, and of enzymes with heme prosthetic groups could be delivered in plasma. Albumin, haptoglobin, hemopexin, and high and low density lipoproteins cooperate to trap the plasma heme, thereby ensuring its complete clearance. Then hemopexin releases the heme into hepatic parenchymal cells only after internalization of the hemopexin‐heme complex by CD91 receptor‐mediated endocytosis. Moreover, α1‐microglobulin contributes to heme degradation by a still unknown mechanism, with the concomitant formation of heterogeneous yellow‐brown kynurenine‐derived chromophores which are very tightly bound to amino acid residues close to the rim of the lipocalin pocket. During hemoglobin synthesis, the erythroid α‐chain hemoglobin‐stabilizing protein specifically binds free α‐hemoglobin subunits limiting the free protein toxicity. Although highly toxic because capable of catalyzing free radical formation, heme is also a major and readily available source of iron for pathogenic organisms. Gram‐negative bacteria pick up the heme‐bound iron through the secretion of a hemophore that takes up either free heme or heme bound to heme‐proteins and transports it to a specific receptor, which, in turn, releases the heme and hence iron into the bacterium. Here, hemoglobin and heme trapping mechanisms are summarized. IUBMB Life, 57: 749‐759, 2005

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“…Evidence exists for the association between haptoglobin levels and inflammatory diseases, and it is proposed that this protein has an anti-inflammatory/ immunomodulatory function (Quaye 2008). In recent years, it has been proposed, on the basis of structural and functional analysis, that haptoglobin is, like clusterin, a secreted molecular chaperone (Ettrich et al 2002;Yerbury et al 2005). If this evidence is correct, then we can add another molecular chaperone to the list of alternative macrophage activators.…”

Section: Gp96mentioning

confidence: 99%

Unfolding the relationship between secreted molecular chaperones and macrophage activation states

Henderson

2009

Cell Stress and Chaperones

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Over the last 20 years, it has emerged that many molecular chaperones and protein-folding catalysts are secreted from cells and function, somewhat in the manner of cytokines, as pleiotropic signals for a variety of cells, with much attention being focused on the macrophage. During the last decade, it has become clear that macrophages respond to bacterial, protozoal, parasitic and host signals to generate phenotypically distinct states of activation. These activation states have been termed 'classical' and 'alternative' and represent not a simple bifurcation in response to external signals but a range of cellular phenotypes. From an examination of the literature, the hypothesis is propounded that mammalian molecular chaperones are able to induce a wide variety of alternative macrophage activation states, and this may be a system for relating cellular or tissue stress to appropriate macrophage responses to restore homeostatic equilibrium.

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Study of Chaperone-Like Activity of Human Haptoglobin: Conformational Changes under Heat Shock Conditions and Localization of Interaction Sites

Cited by 26 publications

References 43 publications

α2-Macroglobulin and Haptoglobin Suppress Amyloid Formation by Interacting with Prefibrillar Protein Species

α2-Macroglobulin and Haptoglobin Suppress Amyloid Formation by Interacting with Prefibrillar Protein Species

Hemoglobin and heme scavenging

Unfolding the relationship between secreted molecular chaperones and macrophage activation states

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