Quality control of protein folding in extracellular space

Yerbury, Justin J.; Stewart, Elise M.; Wyatt, Amy R.; Wilson, Mark R.

doi:10.1038/sj.embor.7400586

Cited by 113 publications

(106 citation statements)

References 49 publications

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“…The Aβ peptide 1-42 (Aβ42) was purchased from Anaspec (USA), dissolved in 60 μL of 1.0 % NH 4 OH and brought to a final concentration of 250 μM using MilliQ water. This stock solution was separated into aliquots and stored at −80 °C until use.…”

Section: Methodsmentioning

confidence: 99%

“…), native proteins can misfold via partially structured intermediates to either disordered amorphous aggregates or ordered amyloid fibrils [3]. Amorphous aggregation occurs by a relatively fast and random process [4][5][6], whereas amyloid fibril formation occurs in a more ordered manner at a slower rate [7]. Protein misfolding which results in aggregate formation can lead to serious biological consequences.…”

Section: Introductionmentioning

confidence: 99%

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Hemin as a generic and potent protein misfolding inhibitor

Carver

et al. 2014

Biochemical and Biophysical Research Communications

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After the embargo period via non-commercial hosting platforms such as their institutional repository  via commercial sites with which Elsevier has an agreement In all cases accepted manuscripts should: link to the formal publication via its DOI  bear a CC-BY-NC-ND license -this is easy to do, click here to find out how  if aggregated with other manuscripts, for example in a repository or other site, be shared in alignment with our hosting policy  not be added to or enhanced in any way to appear more like, or to substitute for, the published journal article AbstractProtein misfolding causes serious biological malfunction, resulting in diseases including Alzheimer's disease, Parkinson's disease and cataract. Molecules which inhibit protein misfolding are a promising avenue to explore as therapeutics for the treatment of these diseases. In the present study, thioflavin T fluorescence and transmission electron microscopy experiments demonstrated that hemin prevents amyloid fibril formation of kappa-casein, amyloid beta peptide, and α-synuclein by blocking β-sheet structure assembly which is essential in fibril aggregation. Further, inhibition of fibril formation by hemin significantly reduces the cytotoxicity caused by fibrillar amyloid beta peptide in vitro. Interestingly, hemin degrades partially formed amyloid fibrils and prevents further aggregation to mature fibrils. Light scattering assay results revealed that hemin also prevents protein amorphous aggregation of alcohol dehydrogenase, catalase and γs-crystallin. In summary, hemin is a potent agent which generically stabilises proteins against aggregation, and has potential as a key molecule for the development of therapeutics for protein misfolding diseases. Highlights Hemin prevents Aβ42, α-synuclein, and RCM-κ-casein forming amyloid fibrils  Hemin inhibits the β-sheet structure formation of Aβ42  Hemin reduces the cell toxicity caused by fibrillar Aβ42  Hemin dissociates partially formed Aβ42 fibrils  Hemin prevents amorphous aggregation by ADH, catalase and γs-crystallin

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Hemin as a generic and potent protein misfolding inhibitor

Carver

et al. 2014

Biochemical and Biophysical Research Communications

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“…[3] We found that the sequences of extracellular proteins have higher intrinsic aggregation propensity than intracellular ones, an observation that has been related to the dilution that occurs upon secretion. [19,20] We also found that disulfide bonds are associated with sequences of high aggregation propensity (Figure 3 g), which suggests that disulfide bonds have co-evolved with protein sequences [21] to minimize their propensity to form potentially toxic amyloid aggregates. This analysis would explain the high prevalence of disulfide bonds in extracellular proteins, where additional protective mechanisms that reduce misfolding and its consequences are likely to play a less significant role than inside the cell.…”

Section: Angewandte Chemiementioning

confidence: 83%

“…This analysis would explain the high prevalence of disulfide bonds in extracellular proteins, where additional protective mechanisms that reduce misfolding and its consequences are likely to play a less significant role than inside the cell. [20,22] The disulfide bonds of lysozyme inhibit the aggregation of this protein into amyloid fibrils by stabilizing the folded state-a fact that can be attributed to the reduction in the entropy of the unfolded state. [11] A partially unfolded state can nevertheless be populated as a result of changes in conditions, as in this work, or by mutations, as in patients with nonneuropathic systemic amyloidosis.…”

Section: Angewandte Chemiementioning

confidence: 99%

Disulfide Bonds Reduce the Toxicity of the Amyloid Fibrils Formed by an Extracellular Protein

et al. 2011

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The misfolding of proteins into amyloid fibrils constitutes the hallmark of many diseases. [1] Although relatively few physicochemical properties of protein sequences-charge, hydrophobicity, patterns of polar and nonpolar residues, and tendency to form secondary structures-are sufficient to rationalize in general terms their relative propensities to form amyloid fibrils, [2,3] other properties can also be important. One example is intramolecular disulfide bonds, which limit the ways in which a polypeptide can be arranged in a fibril through the topological restraints that they impose. Although disulfide bonds are present in 15 % of the human proteome, in 65 % of secreted proteins, and in more than 50 % of those involved in amyloidosis, our understanding of how they influence the properties of amyloid fibrils is limited. [4][5][6] We have examined the formation of fibrils by human lysozyme [7,8] in the presence and absence (Figure 1 a,b) of its native disulfide bonds, and found that they profoundly influence the fibrillar morphology and cytotoxicity.

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“…Based on these and other findings, it has been proposed that CLU forms part of an extracellular protein quality control system that helps to maintain proteostasis [72]. The CLU gene has been identified as an important risk locus for Alzheimer's disease.…”

Section: Chaperone Activity and Proteinase Inhibitionmentioning

confidence: 99%

Clusterin in the eye: An old dog with new tricks at the ocular surface

Fini

Bauskar

Jeong

et al. 2016

Experimental Eye Research

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, M. R. (2016). Clusterin in the eye: an old dog with new tricks at the ocular surface. Experimental Eye Research, Clusterin in the eye: an old dog with new tricks at the ocular surface AbstractThe multifunctional protein clusterin (CLU) was first described in 1983 as a secreted glycoprotein present in ram rete testis fluid that enhanced aggregation ('clustering') of a variety of cells in vitro. It was also independently discovered in a number of other systems. By the early 1990s, CLU was known under many names and its expression had been demonstrated throughout the body, including in the eye. Its homeostatic activities in proteostasis, cytoprotection, and anti-inflammation have been well documented, however its roles in health and disease are still not well understood. CLU is prominent at fluid-tissue interfaces, and in 1996 it was demonstrated to be the most highly expressed transcript in the human cornea, the protein product being localized to the apical layers of the mucosal epithelia of the cornea and conjunctiva. CLU protein is also present in human tears. Using a preclinical mouse model for desiccating stress that mimics human dry eye disease, the authors recently demonstrated that CLU prevents and ameliorates ocular surface barrier disruption by a remarkable sealing mechanism dependent on attainment of a critical all-or-none concentration in the tears. When the CLU level drops below the critical all-or-none threshold, the barrier becomes vulnerable to desiccating stress. CLU binds selectively to the ocular surface subjected to desiccating stress in vivo, and in vitro to LGALS3 (galectin-3), a key barrier component. Positioned in this way, CLU not only physically seals the ocular surface barrier, but it also protects the barrier cells and prevents further damage to barrier structure. CLU depletion from the ocular surface epithelia is seen in a variety of inflammatory conditions in humans and mice that lead to squamous metaplasia and a keratinized epithelium. This suggests that CLU might have a specific role in maintaining mucosal epithelial differentiation, an idea that can now be tested using the mouse model for desiccating stress. Most excitingly, the new findings suggest that CLU could serve as a novel biotherapeutic for dry eye disease. Competing Interests: US patent 9,241,974 B2 entitled "Clusterin pharmaceuticals and treatment methods using the same" (inventors: MEF and SJ), assigned to the University of Southern California, is connected with this work. MEF holds a management position with Proteris Biotech, Inc., Pasadena, CA, which is developing Protearin for dry eye based on clusterin. MRW declares that he has no competing interests. Page 3 of 65 AbstractThe multifunctional protein clusterin (CLU) was first described in 1983 as a secreted glycoprotein present in ram rete testis fluid that enhanced aggregation ('clustering') of a variety of cells in vitro. It was also independently discovered in a number of other systems. By the early 1990s, CLU was known under many names and its expression had bee...

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Quality control of protein folding in extracellular space

Cited by 113 publications

References 49 publications

Hemin as a generic and potent protein misfolding inhibitor

Hemin as a generic and potent protein misfolding inhibitor

Disulfide Bonds Reduce the Toxicity of the Amyloid Fibrils Formed by an Extracellular Protein

Clusterin in the eye: An old dog with new tricks at the ocular surface

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