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Special Issue "Protein Aggregation"

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology".

Deadline for manuscript submissions: closed (30 November 2011)

Special Issue Editor

Guest Editor
Prof. Dr. Ludmilla A. Morozova-Roche

Department of Medical Biochemistry and Biophysics, Umeå University, Umeå, SE 90781, Sweden
Website | E-Mail
Phone: +46 90 786 5283
Fax: +46 90 786 9795
Interests: amyloid; protein folding; neurodegeneration; inflammation; amyloid diseases

Special Issue Information

Dear Colleagues,

Protein aggregation is the most common and problematic manifestation of protein instability encountered during all stages of protein purification and applications. The formation of unstructured aggregates effectively reduces the quantity of functional compounds in solutions. If protein aggregates are not eliminated by clearance mechanisms from the body, the accumulation of protein deposits is associated with growing number of protein conformational diseases. Among proteins aggregates the structured aggregation involving the formation of cross-beta-sheet containing amyloid fibrils and oligomers received particular attention being a leading course of age-related degenerative amyloid diseases. Evidence accumulated that in some cases the regulated protein aggregation can fulfill useful functions of polypeptide storage or sequestration and minimization of diffusion of highly reactive and toxic species. As a result the protein aggregation became the central theme of much current research aimed at understanding the mechanisms underlying this process and measures increasing proteins stability and reducing the propensity of the spontaneous and often undesirable aggregation. Here we present the collection of articles presenting the broad overview of the state of this rapidly developing field and the challenges met by using current knowledge of the mechanisms of protein molecular assemblies and stability.

Prof. Dr. Ludmilla A. Morozova-Roche
Guest Editor

Keywords

  • protein aggregation
  • amyloid formation
  • self-assembly
  • stability
  • conformational plasticity
  • nucleation
  • inhibition

Published Papers (8 papers)

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Research

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Open AccessArticle The Effect of Osmolytes on Protein Fibrillation
Int. J. Mol. Sci. 2012, 13(3), 3801-3819; doi:10.3390/ijms13033801
Received: 9 February 2012 / Revised: 10 March 2012 / Accepted: 13 March 2012 / Published: 21 March 2012
Cited by 18 | PDF Full-text (413 KB) | HTML Full-text | XML Full-text
Abstract
Osmolytes are small molecules that are exploited by cells as a protective system against stress conditions. They favour compact protein states which makes them stabilize globular proteins in vitro and promote folding. Conversely, this preference for compact states promotes aggregation of unstructured proteins.
[...] Read more.
Osmolytes are small molecules that are exploited by cells as a protective system against stress conditions. They favour compact protein states which makes them stabilize globular proteins in vitro and promote folding. Conversely, this preference for compact states promotes aggregation of unstructured proteins. Here we combine a brief review of the effect of osmolytes on protein fibrillation with a report of the effect of osmolytes on the unstructured peptide hormone glucagon. Our results show that osmolytes either accelerate the fibrillation kinetics or leave them unaffected, with the exception of the osmolyte taurine. Furthermore, the osmolytes that affected the shape of the fibrillation time profile led to fibrils with different structure as revealed by CD. The structural changes induced by Pro, Ser and choline-O-sulfate could be due to specific osmolytes binding to the peptides, stabilizing an otherwise labile fibrillation intermediate. Full article
(This article belongs to the Special Issue Protein Aggregation)
Open AccessArticle Nanoscopic and Photonic Ultrastructural Characterization of Two Distinct Insulin Amyloid States
Int. J. Mol. Sci. 2012, 13(2), 1461-1480; doi:10.3390/ijms13021461
Received: 16 November 2011 / Revised: 11 January 2012 / Accepted: 13 January 2012 / Published: 1 February 2012
Cited by 4 | PDF Full-text (528 KB) | HTML Full-text | XML Full-text
Abstract
Two different conformational isoforms or amyloid strains of insulin with different cytotoxic capacity have been described previously. Herein these filamentous and fibrillar amyloid states of insulin were investigated using biophysical and spectroscopic techniques in combination with luminescent conjugated oligothiophenes (LCO). This new class
[...] Read more.
Two different conformational isoforms or amyloid strains of insulin with different cytotoxic capacity have been described previously. Herein these filamentous and fibrillar amyloid states of insulin were investigated using biophysical and spectroscopic techniques in combination with luminescent conjugated oligothiophenes (LCO). This new class of fluorescent probes has a well defined molecular structure with a distinct number of thiophene units that can adopt different dihedral angles depending on its binding site to an amyloid structure. Based on data from surface charge, hydrophobicity, fluorescence spectroscopy and imaging, along with atomic force microscopy (AFM), we deduce the ultrastructure and fluorescent properties of LCO stained insulin fibrils and filaments. Combined total internal reflection fluorescence microscopy (TIRFM) and AFM revealed rigid linear fibrous assemblies of fibrils whereas filaments showed a short curvilinear morphology which assemble into cloudy deposits. All studied LCOs bound to the filaments afforded more blue-shifted excitation and emission spectra in contrast to those corresponding to the fibril indicating a different LCO binding site, which was also supported by less efficient hydrophobic probe binding. Taken together, the multi-tool approach used here indicates the power of ultrastructure identification applying AFM together with LCO fluorescence interrogation, including TIRFM, to resolve structural differences between amyloid states. Full article
(This article belongs to the Special Issue Protein Aggregation)
Open AccessArticle Monitoring Insulin Aggregation via Capillary Electrophoresis
Int. J. Mol. Sci. 2011, 12(12), 9369-9388; doi:10.3390/ijms12129369
Received: 22 October 2011 / Revised: 6 December 2011 / Accepted: 12 December 2011 / Published: 14 December 2011
Cited by 7 | PDF Full-text (621 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Early stages of insulin aggregation, which involve the transient formation of oligomeric aggregates, are an important aspect in the progression of Type II diabetes and in the quality control of pharmaceutical insulin production. This study is the first to utilize capillary electrophoresis (CE)
[...] Read more.
Early stages of insulin aggregation, which involve the transient formation of oligomeric aggregates, are an important aspect in the progression of Type II diabetes and in the quality control of pharmaceutical insulin production. This study is the first to utilize capillary electrophoresis (CE) with ultraviolet (UV) detection to monitor insulin oligomer formation at pH 8.0 and physiological ionic strength. The lag time to formation of the first detected species in the aggregation process was evaluated by UV-CE and thioflavin T (ThT) binding for salt concentrations from 100 mM to 250 mM. UV-CE had a significantly shorter (5–8 h) lag time than ThT binding (15–19 h). In addition, the lag time to detection of the first aggregated species via UV-CE was unaffected by salt concentration, while a trend toward an increased lag time with increased salt concentration was observed with ThT binding. This result indicates that solution ionic strength impacts early stages of aggregation and β-sheet aggregate formation differently. To observe whether CE may be applied for the analysis of biological samples containing low insulin concentrations, the limit of detection using UV and laser induced fluorescence (LIF) detection modes was determined. The limit of detection using LIF-CE, 48.4 pM, was lower than the physiological insulin concentration, verifying the utility of this technique for monitoring biological samples. LIF-CE was subsequently used to analyze the time course for fluorescein isothiocyanate (FITC)-labeled insulin oligomer formation. This study is the first to report that the FITC label prevented incorporation of insulin into oligomers, cautioning against the use of this fluorescent label as a tag for following early stages of insulin aggregation. Full article
(This article belongs to the Special Issue Protein Aggregation)
Open AccessArticle Nucleated Polymerisation in the Presence of Pre-Formed Seed Filaments
Int. J. Mol. Sci. 2011, 12(9), 5844-5852; doi:10.3390/ijms12095844
Received: 2 August 2011 / Revised: 30 August 2011 / Accepted: 30 August 2011 / Published: 9 September 2011
Cited by 22 | PDF Full-text (328 KB) | HTML Full-text | XML Full-text
Abstract
We revisit the classical problem of nucleated polymerisation and derive a range of exact results describing polymerisation in systems intermediate between the well-known limiting cases of a reaction starting from purely soluble material and for a reaction where no new growth nuclei are
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We revisit the classical problem of nucleated polymerisation and derive a range of exact results describing polymerisation in systems intermediate between the well-known limiting cases of a reaction starting from purely soluble material and for a reaction where no new growth nuclei are formed. Full article
(This article belongs to the Special Issue Protein Aggregation)

Review

Jump to: Research

Open AccessReview Unraveling the Early Events of Amyloid-β Protein (Aβ) Aggregation: Techniques for the Determination of Aβ Aggregate Size
Int. J. Mol. Sci. 2012, 13(3), 3038-3072; doi:10.3390/ijms13033038
Received: 20 December 2011 / Revised: 9 February 2012 / Accepted: 23 February 2012 / Published: 7 March 2012
Cited by 31 | PDF Full-text (1511 KB) | HTML Full-text | XML Full-text
Abstract
The aggregation of proteins into insoluble amyloid fibrils coincides with the onset of numerous diseases. An array of techniques is available to study the different stages of the amyloid aggregation process. Recently, emphasis has been placed upon the analysis of oligomeric amyloid species,
[...] Read more.
The aggregation of proteins into insoluble amyloid fibrils coincides with the onset of numerous diseases. An array of techniques is available to study the different stages of the amyloid aggregation process. Recently, emphasis has been placed upon the analysis of oligomeric amyloid species, which have been hypothesized to play a key role in disease progression. This paper reviews techniques utilized to study aggregation of the amyloid-β protein (Aβ) associated with Alzheimer’s disease. In particular, the review focuses on techniques that provide information about the size or quantity of oligomeric Aβ species formed during the early stages of aggregation, including native-PAGE, SDS-PAGE, Western blotting, capillary electrophoresis, mass spectrometry, fluorescence correlation spectroscopy, light scattering, size exclusion chromatography, centrifugation, enzyme-linked immunosorbent assay, and dot blotting. Full article
(This article belongs to the Special Issue Protein Aggregation)
Open AccessReview Pro-Inflammatory S100A8 and S100A9 Proteins: Self-Assembly into Multifunctional Native and Amyloid Complexes
Int. J. Mol. Sci. 2012, 13(3), 2893-2917; doi:10.3390/ijms13032893
Received: 9 January 2012 / Revised: 21 February 2012 / Accepted: 22 February 2012 / Published: 5 March 2012
Cited by 36 | PDF Full-text (704 KB) | HTML Full-text | XML Full-text
Abstract
S100A8 and S100A9 are EF-hand Ca2+ binding proteins belonging to the S100 family. They are abundant in cytosol of phagocytes and play critical roles in numerous cellular processes such as motility and danger signaling by interacting and modulating the activity of target
[...] Read more.
S100A8 and S100A9 are EF-hand Ca2+ binding proteins belonging to the S100 family. They are abundant in cytosol of phagocytes and play critical roles in numerous cellular processes such as motility and danger signaling by interacting and modulating the activity of target proteins. S100A8 and S100A9 expression levels increased in many types of cancer, neurodegenerative disorders, inflammatory and autoimmune diseases and they are implicated in the numerous disease pathologies. The Ca2+ and Zn2+-binding properties of S100A8/A9 have a pivotal influence on their conformation and oligomerization state, including self-assembly into homo- and heterodimers, tetramers and larger oligomers. Here we review how the unique chemical and conformational properties of individual proteins and their structural plasticity at the quaternary level account for S100A8/A9 functional diversity. Additional functional diversification occurs via non-covalent assembly into oligomeric and fibrillar amyloid complexes discovered in the aging prostate and reproduced in vitro. This process is also regulated by Ca2+and Zn2+-binding and effectively competes with the formation of the native complexes. High intrinsic amyloid-forming capacity of S100A8/A9 proteins may lead to their amyloid depositions in numerous ailments characterized by their elevated expression patterns and have additional pathological significance requiring further thorough investigation. Full article
(This article belongs to the Special Issue Protein Aggregation)
Open AccessReview The Slowly Aggregating Salmon Calcitonin: A Useful Tool for the Study of the Amyloid Oligomers Structure and Activity
Int. J. Mol. Sci. 2011, 12(12), 9277-9295; doi:10.3390/ijms12129277
Received: 28 October 2011 / Revised: 17 November 2011 / Accepted: 24 November 2011 / Published: 13 December 2011
Cited by 9 | PDF Full-text (3581 KB) | HTML Full-text | XML Full-text
Abstract
Amyloid proteins of different aminoacidic composition share the tendency to misfold and aggregate in a similar way, following common aggregation steps. The process includes the formation of dimers, trimers, and low molecular weight prefibrillar oligomers, characterized by the typical morphology of globules less
[...] Read more.
Amyloid proteins of different aminoacidic composition share the tendency to misfold and aggregate in a similar way, following common aggregation steps. The process includes the formation of dimers, trimers, and low molecular weight prefibrillar oligomers, characterized by the typical morphology of globules less than 10 nm diameter. The globules spontaneously form linear or annular structures and, eventually, mature fibers. The rate of this process depends on characteristics intrinsic to the different proteins and to environmental conditions (i.e., pH, ionic strength, solvent composition, temperature). In the case of neurodegenerative diseases, it is now generally agreed that the pathogenic aggregates are not the mature fibrils, but the intermediate, soluble oligomers. However, the molecular mechanism by which these oligomers trigger neuronal damage is still unclear. Inparticular, it is not clear if there is a peculiar structure at the basis of the neurotoxic effect and how this structure interacts with neurons. This review will focus on the results we obtained using salmon Calcitonin, an amyloid protein characterized by a very slow aggregation rate, which allowed us to closely monitor the aggregation process. We used it as a tool to investigate the characteristics of amyloid oligomers formation and their interactions with neuronal cells. Our results indicate that small globules of about 6 nm could be the responsible for the neurotoxic effects. Moreover, our data suggest that the rich content in lipid rafts of neuronal cell plasma membrane may render neurons particularly vulnerable to the amyloid protein toxic effect. Full article
(This article belongs to the Special Issue Protein Aggregation)
Figures

Open AccessReview Active Protein Aggregates Produced in Escherichia coli
Int. J. Mol. Sci. 2011, 12(11), 8275-8287; doi:10.3390/ijms12118275
Received: 12 October 2011 / Revised: 11 November 2011 / Accepted: 11 November 2011 / Published: 22 November 2011
Cited by 23 | PDF Full-text (557 KB) | HTML Full-text | XML Full-text
Abstract
Since recombinant proteins are widely used in industry and in research, the need for their low-cost production is increasing. Escherichia coli is one of the best known and most often used host organisms for economical protein production. However, upon over-expression, protein aggregates called
[...] Read more.
Since recombinant proteins are widely used in industry and in research, the need for their low-cost production is increasing. Escherichia coli is one of the best known and most often used host organisms for economical protein production. However, upon over-expression, protein aggregates called inclusion bodies (IBs) are often formed. Until recently IBs formation represented a bottleneck in protein production as they were considered as deposits of inactive proteins. However, recent studies show that by choosing the appropriate host strain and designing an optimal production process, IBs composed from properly folded and biologically active recombinant proteins can be prepared. Such active protein particles can be further used for the isolation of pure proteins or as whole active protein particles in various biomedical and other applications. Therefore interest in understanding the mechanisms of their formation as well as their properties is increasing. Full article
(This article belongs to the Special Issue Protein Aggregation)

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