Open Access. Powered by Scholars. Published by Universities.®
Physical Sciences and Mathematics Commons™
Open Access. Powered by Scholars. Published by Universities.®
- Keyword
-
- Extracellular Protein Homeostasis (16)
- CMMB (14)
- Extracellular (6)
- Clusterin (5)
- Chaperones (3)
-
- Protein (3)
- Amyloid (2)
- Chaperone (2)
- Clearance (2)
- Formation (2)
- Other (2)
- Proteins (2)
- Toxicity (2)
- 1 (1)
- 42 (1)
- Abundant (1)
- Alzheimer (1)
- Alzheimer’s disease. (1)
- Amyloids (1)
- ApoJ (1)
- Apolipoprotein (1)
- Beta (1)
- Cancer (1)
- Cell (1)
- Cerebrospinal (1)
- Characterization (1)
- Client (1)
- Clients (1)
- Complexes (1)
- Confer (1)
- File Type
Articles 1 - 18 of 18
Full-Text Articles in Physical Sciences and Mathematics
Instant Insight: Think Outside The Cell, Mark R. Wilson, Justin J. Yerbury
Instant Insight: Think Outside The Cell, Mark R. Wilson, Justin J. Yerbury
Mark R Wilson
Proteins perform many different functions critical for life, from building our muscle structure to digesting our food. These large biological molecules each have a unique three-dimensional shape which they require to perform their function. In protein deposition diseases (PDDs), however, a disease-specific protein molecule unfolds from its normal shape and assembles together with like molecules into insoluble rod-shaped fibrils. These protein deposits can be found in the brain, skeletal tissue and various organs; in some cases they may become large enough to disrupt tissue structure and function.
Stress-Induced Retrotranslocation Of Clusterin/Apoj Into The Cytosol, P Nizard, Suzanne Tetley, Y Le Drean, T Watrin, P Le Goff, Mark R. Wilson, Denis Michel
Stress-Induced Retrotranslocation Of Clusterin/Apoj Into The Cytosol, P Nizard, Suzanne Tetley, Y Le Drean, T Watrin, P Le Goff, Mark R. Wilson, Denis Michel
Mark R Wilson
Clusterin is a usually secreted glycoprotein with chaperone properties. Recently, it has been suggested that clusterin isoforms reside in the nuclear and cytosolic compartments of human cell types, where they can influence various cellular programs including DNA repair, transcription and apoptosis. Several mechanisms have been proposed to explain this atypical location, including alternative transcription initiation and alternative splicing. However none of these have been unequivocally established as occurring in live cells. Here we provide direct experimental evidence that in live intact cells, under certain stress conditions, clusterin can evade the secretion pathway and reach the cytosol. This was demonstrated using …
Macroglobulin And Haptoglobin Suppress Amyloid Formation By Interacting With Prefibrillar Protein Species, Justin J. Yerbury, Janet R. Kumita, Sarah Meehan, Christopher M. Dobson, Mark R. Wilson
Macroglobulin And Haptoglobin Suppress Amyloid Formation By Interacting With Prefibrillar Protein Species, Justin J. Yerbury, Janet R. Kumita, Sarah Meehan, Christopher M. Dobson, Mark R. Wilson
Mark R Wilson
α2-Macroglobulin (α2M) 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 α2M and Hp both inhibit the formation of amyloid fibrils from a range of proteins. We also provide evidence that both α2M and Hp interact with prefibrillar …
Clusterin Facilitates In Vivo Clearance Of Extracellular Misfolded Proteins, Amy R. Wyatt, Justin J. Yerbury, Paula Berghofer, I Greguric, Andrew Katsifis, Christopher Dobson, Mark R. Wilson
Clusterin Facilitates In Vivo Clearance Of Extracellular Misfolded Proteins, Amy R. Wyatt, Justin J. Yerbury, Paula Berghofer, I Greguric, Andrew Katsifis, Christopher Dobson, Mark R. Wilson
Mark R Wilson
The extracellular deposition of misfolded proteins is a characteristic of many debilitating age-related disorders. However, little is known about the specific mechanisms that act to suppress this process in vivo. Clusterin (CLU) is an extracellular chaperone that forms stable and soluble complexes with misfolded client proteins. Here we explore the fate of complexes formed between CLU and misfolded proteins both in vitro and in a living organism. We show that proteins injected into rats are cleared more rapidly from circulation when complexed with CLU as a result of their more efficient localisation to the liver and that this clearance is …
Potential Roles Of Abundant Extracellular Chaperones In The Control Of Amyloid Formation And Toxicity, Mark R. Wilson, Justin J. Yerbury, Stephen Poon
Potential Roles Of Abundant Extracellular Chaperones In The Control Of Amyloid Formation And Toxicity, Mark R. Wilson, Justin J. Yerbury, Stephen Poon
Mark R Wilson
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 …
Extracellular Chaperones Modulate The Effects Of Alzheimer's Patient Cerebrospinal Fluid On A Beta(1-42) Toxicity And Uptake , Justin J. Yerbury, Mark R. Wilson
Extracellular Chaperones Modulate The Effects Of Alzheimer's Patient Cerebrospinal Fluid On A Beta(1-42) Toxicity And Uptake , Justin J. Yerbury, Mark R. Wilson
Mark R Wilson
Alzheimer's disease is characterised by the inappropriate death of brain cells and accumulation of the A beta peptide in the brain. Thus, it is possible that there are fundamental differences between Alzheimer's disease patients and healthy individuals in their abilities to clear A beta from brain fluid and to protect neurons from A beta toxicity. In the present study, we examined (1) the cytotoxicity of Alzheimer's disease cerebrospinal fluid (CSF) compared to control CSF, (2) the ability of Alzheimer's disease and control CSF to protect cells from A beta toxicity and to promote cell-mediated clearance of A beta and lastly …
Quality Control Of Protein Folding In Extracellular Space, J. J. Yerbury, E. M. Stewart, A. R. Wyatt, M. R. Wilson
Quality Control Of Protein Folding In Extracellular Space, J. J. Yerbury, E. M. Stewart, A. R. Wyatt, M. R. Wilson
Mark R Wilson
The pathologies of many serious human diseases are thought to develop from the effects of intra- or extracellular aggregates of non-native proteins. Inside cells, chaperone and protease systems regulate protein folding; however, little is known about any corresponding mechanisms that operate extracellularly. The identification of these mechanisms is important for the development of new disease therapies. This review briefly discusses the consequences of protein misfolding, the intracellular mechanisms that control folding and the potential corresponding extracellular control processes. Finally, a new speculative model is described, which proposes that newly discovered extracellular chaperones bind to exposed regions of hydrophobicity on non-native, …
Extracellular Chaperones And Amyloids, Mark R. Wilson, Justin J. Yerbury, Stephen Poon
Extracellular Chaperones And Amyloids, Mark R. Wilson, Justin J. Yerbury, Stephen Poon
Mark R Wilson
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 …
Small Heat-Shock Proteins And Clusterin: Intra- And Extracellular Molecular Chaperones With A Common Mechanism Of Action And Function, J. A. Carver, A. Rekas, D. C. Thorn, M. R. Wilson
Small Heat-Shock Proteins And Clusterin: Intra- And Extracellular Molecular Chaperones With A Common Mechanism Of Action And Function, J. A. Carver, A. Rekas, D. C. Thorn, M. R. Wilson
Mark R Wilson
Small heat-shock proteins (sHsps) and clusterin are molecular chaperones that share many functional similarities despite their lack of significant sequence similarity. These functional similarities, and some differences, are discussed. sHsps are ubiquitous intracellular proteins whereas clusterin is generally found extracellularly. Both chaperones potently prevent the amorphous aggregation and precipitation of target proteins under stress conditions such as elevated temperature, reduction and oxidation. In doing so, they act on the slow off-folding protein pathway. The conformational dynamism and aggregated state of both proteins may be crucial for their chaperone function. Subunit exchange is likely to be important in regulating chaperone action; …
Clusterin Is An Extracellular Chaperone That Specifically Interacts With Slowly Aggregating Proteins On Their Off-Folding Pathway, Stephen Poon, T. M. Treweek, Mark R. Wilson, Simon B. Easterbrook-Smith, John A. Carver
Clusterin Is An Extracellular Chaperone That Specifically Interacts With Slowly Aggregating Proteins On Their Off-Folding Pathway, Stephen Poon, T. M. Treweek, Mark R. Wilson, Simon B. Easterbrook-Smith, John A. Carver
Mark R Wilson
Clusterin is an extracellular mammalian chaperone protein which inhibits stress-induced precipitation of many different proteins. The conformational state(s) of proteins that interact with clusterin and the stage(s) along the folding and off-folding (precipitation-bound) pathways where this interaction occurs were previously unknown. We investigated this by examining the interactions of clusterin with different structural forms of α-lactalbumin, γ-crystallin and lysozyme. When assessed by ELISA and native gel electrophoresis, clusterin did not bind to various stable, intermediately folded states of α-lactalbumin nor to the native form of this protein, but did bind to and inhibit the slow precipitation of reduced α-lactalbumin. Reduction-induced …
Clusterin Interacts With Paclitaxel And Confer Paclitaxel Resistance In Ovarian Cancer, Dong Choon Park, Seung Geun Yeo, Mark R. Wilson, Justin J. Yerbury, Joseph Kwong, William R. Welch, Yang Kyu Choi, Michael J. Birrer, Samuel C. Mok, Kwong-Kwok Wong
Clusterin Interacts With Paclitaxel And Confer Paclitaxel Resistance In Ovarian Cancer, Dong Choon Park, Seung Geun Yeo, Mark R. Wilson, Justin J. Yerbury, Joseph Kwong, William R. Welch, Yang Kyu Choi, Michael J. Birrer, Samuel C. Mok, Kwong-Kwok Wong
Mark R Wilson
Optimal debulking followed by chemotherapy is the standard treatment of managing late-stage ovarian cancer, but chemoresistance is still a major problem. In this study, we compared expression profiles of primary tumor tissue from five long-term (>8 years) and five short-term (years) ovarian cancer survivors and identified clusterin as one of the genes that were significantly up-regulated in short-term survivors. We then evaluated the prognostic significance of clusterin and its possible correlation with chemoresistance in ovarian cancer by immunohistostaining of clusterin in 62 tumor samples from patients with stage III, high-grade serous ovarian cancer. After adjusting for debulking status and …
Apolipoprotein J And Leptin Levels In Patients With Coronary Heart Disease, Mark Wilson, Dimitri Mikhailidis, Maria Poulakou, Christos Tsigris, Despina Perrea, Kosmas Paraskevas, Dimitrios Iliopoulos
Apolipoprotein J And Leptin Levels In Patients With Coronary Heart Disease, Mark Wilson, Dimitri Mikhailidis, Maria Poulakou, Christos Tsigris, Despina Perrea, Kosmas Paraskevas, Dimitrios Iliopoulos
Mark R Wilson
No abstract provided.
Structural Characterization Of Clusterin-Chaperone Client Protein Complexes, Amy Wyatt, Justin Yerbury, Mark Wilson
Structural Characterization Of Clusterin-Chaperone Client Protein Complexes, Amy Wyatt, Justin Yerbury, Mark Wilson
Mark R Wilson
Clusterin (CLU) is a potent extracellular chaperone that inhibits protein aggregation and precipitation otherwise caused by physical or chemical stresses (e.g. heat, reduction). This action involves CLU forming soluble high molecular weight (HMW) complexes with the client protein. Other than their unquantified large size, the physical characteristics of these complexes were previously unknown. In this study, HMW CLU-citrate synthase (CS), HMW CLU-fibrinogen (FGN), and HMW CLU-glutathione S-transferase (GST) complexes were generated in vitro, and their structures studied using size exclusion chromatography (SEC), ELISA, SDS-PAGE, dynamic light scattering (DLS), bisANS fluorescence, and circular dichroism spectrophotometry (CD). Densitometry of …
Identification Of Human Plasma Proteins As Major Clients For The Extracellular Chaperone Clusterin, Amy R. Wyatt, Mark R. Wilson
Identification Of Human Plasma Proteins As Major Clients For The Extracellular Chaperone Clusterin, Amy R. Wyatt, Mark R. Wilson
Mark R Wilson
Clusterin (CLU) is an extracellular chaperone that is likely to play an important role in protein folding quality control. This study identified three deposition disease-associated proteins as major plasma clients for clusterin by studying CLU-client complexes formed in response to physiologically relevant stress (shear stress, similar to 36 dynes/cm(2) at 37 degrees C). Analysis of plasma samples by size exclusion chromatography indicated that (i) relative to control plasma, stressed plasma contained proportionally more soluble protein species of high molecular weight, and (ii) high molecular weight species were far more abundant when proteins purified by anti-CLU immunoaffinity chromatography from stressed plasma …
Therapeutic Targets In Extracellular Protein Deposition Diseases, Amy R. Wyatt, Justin J. Yerbury, Stephen Poon, Mark R. Wilson
Therapeutic Targets In Extracellular Protein Deposition Diseases, Amy R. Wyatt, Justin J. Yerbury, Stephen Poon, Mark R. Wilson
Mark R Wilson
Many litres of fluids are found outside cells in the human body. These fluids are rich in dissolved proteins that each have a characteristic three dimensional shape, necessary for normal function, which has been attained by the correct folding of their polypeptide chain(s). The structure of these extracellular proteins can be damaged by a variety of environmental stresses (e. g. heat and oxidation) leading to their partial unfolding and aggregation. This in turn can produce toxic soluble aggregates and/or large insoluble protein deposits, either of which can disrupt normal body function (e. g. in Alzheimer's disease and the systemic amyloidoses). …
Roles Of Extracellular Chaperones In Amyloidosis, Amy R. Wyatt, Justin J. Yerbury, Rebecca A. Dabbs, Mark R. Wilson
Roles Of Extracellular Chaperones In Amyloidosis, Amy R. Wyatt, Justin J. Yerbury, Rebecca A. Dabbs, Mark R. Wilson
Mark R Wilson
Extracellular protein misfolding and aggregation underlie many of the most serious amyloidoses including Alzheimer's disease, spongiform encephalopathies and type II diabetes. Despite this, protein homeostasis (proteostasis) research has largely focussed on characterising systems that function to monitor protein conformation and concentration within cells. We are now starting to identify elements of corresponding systems, including an expanding family of secreted chaperones, which exist in the extracellular space. Like their intracellular counterparts, extracellular chaperones are likely to play a central role in systems that maintain proteostasis; however, the precise details of how they participate are only just emerging. It is proposed that …
Clusterin Is A Secreted Mammalian Chaperone, M. R. Wilson, S. B. Easterbrook-Smith
Clusterin Is A Secreted Mammalian Chaperone, M. R. Wilson, S. B. Easterbrook-Smith
Mark R Wilson
[Extract] By any criteria, clusterin is an interesting protein. It was first described in 1983 as a secreted glycoprotein in ram rete testis fluid that enhanced aggregation (“clustering”) of a variety of cells in vitro 1. Many homologues in other species were subsequently discovered. Typically, each “discovery” of clusterin in a different species or by a different research group led to it being assigned another name. By the early 1990s clusterin was known under many aliases 2, some of which persist in the literature. However, the inaugural international workshop on clusterin (Cambridge, 1992) agreed to the name clusterin, in deference …
Phinocytic Loading Of Cytochrome C Into Intact Cells Specifically Induces Caspase-Dependent Permeabilization Of Mitochondria: Evidence For A Cytochrome C Feedback Loop, K. J. Gilmore, H. E. Quinn, M. R. Wilson
Phinocytic Loading Of Cytochrome C Into Intact Cells Specifically Induces Caspase-Dependent Permeabilization Of Mitochondria: Evidence For A Cytochrome C Feedback Loop, K. J. Gilmore, H. E. Quinn, M. R. Wilson
Mark R Wilson
Previous studies introduced cytochrome c into intact cells via the disruptive techniques of microinjection or electroporation to provide support for the hypothesis that, in whole cells, cytochrome c release from mitochondria triggers caspase activation and other degradative changes. However, the types of measurements that could be undertaken with these techniques was limited. We used the simple and relatively gentle technique of pinocytic loading to demonstrate that, in intact cells, cytosolic cytochrome c specifically induced activation of caspase-3- and -9-like enzymes, and a loss of mitochondrial polarization coincident with an increase in mitochondrial permeability. Our results support the prediction from in …