Haptoglobin: The Evolutionary Product of Duplication, Unequal Crossing Over, and Point Mutation

Bowman, Barbara H.; Kurosky, Alexander

doi:10.1007/978-1-4615-8315-8_3

Cited by 312 publications

(313 citation statements)

References 148 publications

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“…Normally, it is present in human plasma at 300-2000 g/ml 35 and CSF at 0.5-2 g/ml. 36 However, the levels of Hp in human plasma are increased up to 8-fold during various physiological stresses (e.g.…”

Section: Haptoglobinmentioning

confidence: 99%

Potential roles of abundant extracellular chaperones in the control of amyloid formation and toxicity

2008

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The in vivo formation of fibrillar proteinaceous deposits called amyloid is associated with more than 40 serious human diseases, collectively referred to as protein deposition diseases. In many cases the amyloid deposits are extracellular and are found associated with newly identified abundant extracellular chaperones (ECs). Evidence is presented suggesting an important regulatory role for ECs in amyloid formation and disposal in the body. A model is presented which proposes that, under normal conditions, ECs stabilize extracellular misfolded proteins by binding to them, and then guide them to specific cell receptors for uptake and subsequent degradation. Thus ECs and their receptors may be critical parts of a quality control system to protect the body 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. Keywords: Extracellular chaperones, receptor-mediated endocytosis, amyloid, protein quality control, aggregate toxicity, fibril formation word statement (for Contents list) plus graphic (note -colour version of below graphic provided separately)Newly identified abundant extracellular chaperones (ECs) may protect the body against dangerously hydrophobic proteins/peptides. This review proposes that ECs stabilize extracellular misfolded proteins by binding to them, and then guide them to specific receptors for uptake and subsequent degradation. SUMMARYThe in vivo formation of fibrillar proteinaceous deposits called amyloid is associated with more than 40 serious human diseases, collectively referred to as protein deposition diseases. In many cases the amyloid deposits are extracellular and are found associated with newly identified abundant extracellular chaperones (ECs). Evidence is presented suggesting an important regulatory role for ECs in amyloid formation and disposal in the body. A model is presented which proposes that, under normal conditions, ECs stabilize extracellular misfolded proteins by binding to them, and then guide them to specific cell receptors for uptake and subsequent degradation. Thus ECs and their receptors may be critical parts of a quality control system to protect the body 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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Section: Haptoglobinmentioning

confidence: 99%

Potential roles of abundant extracellular chaperones in the control of amyloid formation and toxicity

2008

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“…These four proteins share some notable similarities. All four are secreted glycoproteins widely distributed in most physiological fluids, including plasma and CSF (Barrett 1981;Baltz et al, 1982;Bowman and Kurosky 1982;. Moreover, all bind to a broad range of ligands (Barrett 1981;Capiau et al, 1986;Katnik et al, 1987;Aruga et al, 1993;Katnik et al, 1993;Zahedi 1996;Ashton et al, 1997;Langlois et al, 1997;Zahedi 1997;Kurdowska et al, 2000;Wilson and Easterbrook-Smith 2000;Kimura et al, 2001;Sen and Heegaard 2002) and have been found associated with clinical amyloid deposits in vivo (Table (1)) (Powers et al, 1981;Baltz et al, 1982;Van Gool et al, 1993;McHattie and Edington 1999;Calero et al, 2000).…”

Section: Extracellular Chaperonesmentioning

confidence: 99%

“…Haptoglobin (Hp) is a secreted acidic glycoprotein (20% of its total mass is N-linked carbohydrate (Bowman and Kurosky 1982)) produced mainly in the liver and found in most body fluids of humans and other mammals. Normally, it is present in human plasma at 300-2000 µg/ml (Bowman and Kurosky 1982) and CSF at 0.5-2 µg/ml (Sobek and Adam 2003).…”

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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“…These functional differences invariably associate Hp polymorphism with the prevalence and clinical evolution of many autoimmune and inflammatory diseases, including severity of myocardial infarction [14,15]. Hp functions as an antioxidant by virtue of its ability to bind and capture free haemoglobin released into blood plasma [16,17] and thereby prevents the oxidative tissue damage that may be mediated or catalysed by free haemoglobin through the generation of highly reactive oxygen species by the Fenton reaction [18]. Formation of the Hp-Hb complex in vivo has been found to play a role in preventing the Hb-driven generation of hydroxyl radical and lipid peroxidation in areas of inflammation where reactive oxygen species (ROS) promotes endothelial activation and inflammation, leading to endothelial dysfunction [19].…”

mentioning

confidence: 99%

Haptoglobin Polymorphism and Association with Complications in Ghanaian Type 2 Diabetic Patients

et al. 2011

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There is scanty information on the role of genetic factors, especially those relating to haptoglobin (Hp) phenotypes in the expression of complications among diabetes mellitus patients in Ghana. In this study, we investigated whether there is any association between Hp phenotypes and diabetic complications and to determine if association of the Hp phenotypes with diabetic complications in Ghanaian diabetics differ from those in Caucasians. A total of 398 participants were randomly recruited into the study. These comprised diabetic patients numbering 290 attending a diabetes Clinic in Ghana and 108 non-diabetic controls from the same community. Analyses of the results indicate that most of the diabetics with complications were of the Hp 2-2 (35%) and Hp 2-1 (23.9%) phenotypes. Fewer diabetics were found to be of the Hp 2-1 M phenotype. The controls were mostly of Hp 1-1 and Hp 2-1 M phenotypes. The odds ratio of having complications in a diabetic with an Hp 2-2 phenotype was 18.27 times greater than that for Hp 0-0. Hp 2-2 phenotype with its poor antioxidant activity may therefore be a useful predictor for the propensity of an individual to develop diabetes complications.

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Haptoglobin: The Evolutionary Product of Duplication, Unequal Crossing Over, and Point Mutation

Cited by 312 publications

References 148 publications

Potential roles of abundant extracellular chaperones in the control of amyloid formation and toxicity

Potential roles of abundant extracellular chaperones in the control of amyloid formation and toxicity

Extracellular Chaperones and Amyloids

Haptoglobin Polymorphism and Association with Complications in Ghanaian Type 2 Diabetic Patients

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