Chaperone-Like Activity of Human Haptoglobin: Similarity with α-Crystallin

Pavlı́ček, Zdeněk; Ettrich, Rüdiger

doi:10.1135/cccc19990717

Cited by 14 publications

(14 citation statements)

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“…Like clusterin, all three haptoglobin phenotypes have been shown to inhibit stressinduced amorphous protein aggregation of a wide range of client proteins in vitro (84,85), and immunodepletion of haptoglobin from human blood plasma has been shown to render plasma proteins susceptible to precipitation (85). Complexation with hemoglobin reduces but does not abolish the chaperone activity of haptoglobin, which supports that the binding sites on haptoglobin for hemoglobin and misfolded client proteins are discrete (74,86).…”

Section: Haptoglobinmentioning

confidence: 92%

Extracellular Chaperones and Proteostasis

Wyatt

Yerbury

Ecroyd

et al. 2013

Annu. Rev. Biochem.

161

173

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There is a family of currently untreatable serious human diseases that arise from the inappropriate misfolding and aggregation of extracellular proteins. At present our understanding of mechanisms that operate to maintain proteostasis in extracellular body fluids is limited but has significantly advanced with the discovery of a small but growing family of constitutively secreted extracellular chaperones (ECs). The available evidence strongly suggests that these chaperones act as both sensors and disposal-mediators of misfolded proteins in extracellular fluids, thereby normally protecting us from disease pathologies. It is critically important to further increase our understanding of the mechanisms that operate to effect extracellular proteostasis, as this will be essential knowledge upon which to base the development of effective therapies for some of the world's most debilitating, costly and intractable diseases.

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Section: Haptoglobinmentioning

confidence: 92%

Extracellular Chaperones and Proteostasis

Wyatt

Yerbury

Ecroyd

et al. 2013

Annu. Rev. Biochem.

161

173

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“…Human Hp specifically inhibits the precipitation of a wide variety of proteins induced by a range of stresses (Pavlicek and Ettrich 1999;. All three human Hp phenotypes exert this chaperone action, although at equivalent mass concentrations, at least for one substrate protein tested, Hp1-1 was the most efficient.…”

Section: Haptoglobinmentioning

confidence: 99%

Extracellular Chaperones and Amyloids

Wilson¹,

Yerbury²,

Poon³

2008

Heat Shock Proteins and the Brain: Implications for Neurodegenerative Diseases and Neuroprotection

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The pathology of more than 40 human degenerative diseases is associated with fibrillar proteinaceous deposits called amyloid. Collectively referred to as protein deposition diseases, many of these affect the brain and the central nervous system. In many cases the amyloid deposits are extracellular and are found associated with newly identified abundant extracellular chaperones (ECs). Evidence is discussed which suggests an important regulatory role for ECs in amyloid formation and disposal in vivo. This is emerging as an exciting field. A model is presented in which it is proposed that, under normal conditions, ECs stabilize extracellular misfolded proteins by binding to them, and then guide them to specific receptors for uptake and subsequent degradation. In this scenario, EC receptors are a critical part of a quality control system which protects the brain against dangerously hydrophobic proteins/peptides. However, it also appears possible that in the presence of a high molar excess of misfolded protein, such as might occur during disease, the limited amounts of ECs available may actually exacerabate pathology. Further advances in understanding of the mechanisms that control extracellular protein folding are likely to identify new strategies for effective disease therapies. ABSTRACTThe pathology of more than 40 human degenerative diseases is associated with fibrillar proteinaceous deposits called amyloid. Collectively referred to as protein deposition diseases, many of these affect the brain and the central nervous system. In many cases the amyloid deposits are extracellular and are found associated with newly identified abundant extracellular chaperones (ECs). Evidence is discussed which suggests an important regulatory role for ECs in amyloid formation and disposal in vivo. This is emerging as an exciting field. A model is presented in which it is proposed that, under normal conditions, ECs stabilize extracellular misfolded proteins by binding to them, and then guide them to specific receptors for uptake and subsequent degradation. In this scenario, EC receptors are a critical part of a quality control system which protects the brain against dangerously hydrophobic proteins/peptides. However, it also appears possible that in the presence of a high molar excess of misfolded protein, such as might occur during disease, the limited amounts of ECs available may actually exacebate pathology. Further advances in understanding of the mechanisms that control extracellular protein folding are likely to identify new strategies for effective disease therapies.

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“…Human Hp specifically inhibits the precipitation of a wide variety of proteins induced by a range of stresses (10,26). Like clusterin, Hp forms stable and soluble high molecular weight complexes with misfolded proteins but has no independent ability to refold misfolded proteins.…”

mentioning

confidence: 99%

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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Chaperone-Like Activity of Human Haptoglobin: Similarity with α-Crystallin

Cited by 14 publications

References 1 publication

Extracellular Chaperones and Proteostasis

Extracellular Chaperones and Proteostasis

Extracellular Chaperones and Amyloids

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

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