Necessity of regulatory guidelines for the development of amyloid based biomaterials

2021 ◽  
Author(s):  
Vijay Kumar ◽  
Nabodita Sinha ◽  
Ashwani Kumar Thakur
Keyword(s):  
Protein Homeostasis ◽  
Regulatory Guidelines ◽  
Folded Proteins ◽  
Amyloid Diseases ◽  
Β Sheet

Amyloid diseases are caused due to protein homeostasis failure where incorrectly folded proteins/peptides form cross-β-sheet rich amyloid fibrillar structures. Besides proteins/peptides, small metabolite assemblies also exhibit amyloid-like features. These structures...

Effect of curcumin on amyloidogenic property of molten globule-like intermediate state of 2,5-diketo-d-gluconate reductase A

2009 ◽  
Vol 390 (10) ◽  
Author(s):  
Nandini Sarkar ◽  
Abhay Narain Singh ◽  
Vikash Kumar Dubey
Keyword(s):  
Protein Concentration ◽  
Molten Globule ◽  
Molar Ratio ◽  
Amyloid Formation ◽  
Molten Globule State ◽  
Force Microscopy ◽  
Atomic Force ◽  
Sheet Structure ◽  
Amyloid Diseases ◽  
Β Sheet

Abstract We identified a molten globule-like intermediate of 2,5-diketo-d-gluconate reductase A (DKGR) at pH 2.5, which has a prominent β-sheet structure. The molten globule state of the protein shows amyloidogenic property >50 μm protein concentration. Interestingly, a 1:1 molar ratio of curcumin prevents amyloid formation as shown by the Thioflavin-T assay and atomic force microscopy. To the best of our knowledge, this is the first report on amyloid formation by an (α/β)8-barrel protein. The results presented here indicate that the molten globule state has an important role in amyloid formation and potential application of curcumin in protein biotechnology as well as therapeutics against amyloid diseases.

scholarly journals Pulse labeling reveals the tail end of protein folding by proteome profiling

2021 ◽  
Author(s):  
Mang Zhu ◽  
Erich R. Kuechler ◽  
Nikolay Stoynov ◽  
Joerg Gsponer ◽  
Thibault Mayor
Keyword(s):  
Mass Spectrometry ◽  
Protein Folding ◽  
Heat Stress ◽  
Protein Complexes ◽  
Protein Sequences ◽  
Protein Homeostasis ◽  
Native State ◽  
Binding Motifs ◽  
Specific Subset ◽  
Β Sheet

SummaryAccurate and efficient folding of nascent protein sequences into their native state requires support from the protein homeostasis network. Herein we probed which newly translated proteins are less thermostable to infer which polypeptides require more time to fold within the proteome. Specifically, we determined which of these proteins were more susceptible to misfolding and aggregation under heat stress using pulse SILAC coupled mass spectrometry. These proteins are abundant, short, and highly structured. Notably these proteins display a tendency to form β-sheet structures, a configuration which typically requires more time for folding, and were enriched for Hsp70/Ssb and TRiC/CCT binding motifs, suggesting a higher demand for chaperone-assisted folding. These polypeptides were also more often components of stable protein complexes in comparison to other proteins. All evidence combined suggests that a specific subset of newly translated proteins requires more time following synthesis to reach a thermostable native state in the cell.

scholarly journals A short commentary on indents and edges of β-sheets

2019 ◽  
Author(s):  
Harshavardhan Khare ◽  
Suryanarayanarao Ramakumar
Keyword(s):  
Short Length ◽  
The Other ◽  
Stacking Interactions ◽  
Design Strategies ◽  
Hydrophobic Residues ◽  
Short Commentary ◽  
Β Sheets ◽  
Folded Proteins ◽  
Polypeptide Chains ◽  
Β Sheet

Abstractβ-sheets in proteins are formed by extended polypeptide chains, called β-strands. While there is a general consensus on two types of β-strands, viz. ‘edge strands’ (or ‘edges’) and ‘inner strands’ (or ‘central strands’), the possibility of distinguishing between different regions of inner strands remains less explored. In this paper, we address the portions of inner strands of β-sheets that stick out on either or both sides. We call these portions the ‘indent strands’ or ‘indents’ because they give the typical indented appearance to β-sheets. Similar to the edge strands, the indent strands also have β-bridge partner residues on one side while the other side is still open for backbone hydrogen bonds. Despite this similarity, the indent strands differ from the edge strands in terms of various properties such as β-bulges and amino acid composition due to their localization within β-sheets and therefore within folded proteins to certain extent. The localization of indents and edges within folded proteins seems to govern the strategies deployed to deter unhindered β-sheet propagation through β-strand stacking interactions. Our findings suggest that, edges and indents differ in their strategies to avoid further β-strand stacking. Short length itself is a good strategy to avoid stacking and a majority of indents are two residue or shorter in length. Edge strands on the other hand are overall longer. While long edges are known to use various negative design strategies like β-bulges, prolines, strategically placed charges, inward-pointing charged side chains and loop coverage to avoid further β-strand stacking, long indents seem to favor mechanisms such as enrichment in flexible residues with high solvation potential and depletion in hydrophobic residues in response to their less solvent exposed nature. Such subtle differences between indents and edges could be leveraged for designing novel β-sheet architectures.

scholarly journals Organismal Protein Homeostasis Mechanisms

Genetics ◽  
2020 ◽  
Vol 215 (4) ◽  
pp. 889-901 ◽  
Author(s):  
Thorsten Hoppe ◽  
Ehud Cohen
Keyword(s):  
Quality Control ◽  
Protein Quality ◽  
Protein Homeostasis ◽  
Control Mechanisms ◽  
Dynamic Regulation ◽  
C Elegans ◽  
Selective Degradation ◽  
Proteotoxic Stress ◽  
Health And Disease ◽  
Folded Proteins

Sustaining a healthy proteome is a lifelong challenge for each individual cell of an organism. However, protein homeostasis or proteostasis is constantly jeopardized since damaged proteins accumulate under proteotoxic stress that originates from ever-changing metabolic, environmental, and pathological conditions. Proteostasis is achieved via a conserved network of quality control pathways that orchestrate the biogenesis of correctly folded proteins, prevent proteins from misfolding, and remove potentially harmful proteins by selective degradation. Nevertheless, the proteostasis network has a limited capacity and its collapse deteriorates cellular functionality and organismal viability, causing metabolic, oncological, or neurodegenerative disorders. While cell-autonomous quality control mechanisms have been described intensely, recent work on Caenorhabditis elegans has demonstrated the systemic coordination of proteostasis between distinct tissues of an organism. These findings indicate the existence of intricately balanced proteostasis networks important for integration and maintenance of the organismal proteome, opening a new door to define novel therapeutic targets for protein aggregation diseases. Here, we provide an overview of individual protein quality control pathways and the systemic coordination between central proteostatic nodes. We further provide insights into the dynamic regulation of cellular and organismal proteostasis mechanisms that integrate environmental and metabolic changes. The use of C. elegans as a model has pioneered our understanding of conserved quality control mechanisms important to safeguard the organismal proteome in health and disease.

Amyloid diseases of yeast: prions are proteins acting as genes

2014 ◽  
Vol 56 ◽  
pp. 193-205 ◽  
Author(s):  
Reed B. Wickner ◽  
Herman K. Edskes ◽  
David A. Bateman ◽  
Amy C. Kelly ◽  
Anton Gorkovskiy ◽  
...  
Keyword(s):  
Normal Form ◽  
Biological Properties ◽  
Podospora Anserina ◽  
Nmr Studies ◽  
Hydrophobic Residues ◽  
Yeast Prions ◽  
Amyloid A ◽  
Pathological Disease ◽  
Amyloid Diseases ◽  
Β Sheet

The unusual genetic properties of the non-chromosomal genetic elements [URE3] and [PSI+] led to them being identified as prions (infectious proteins) of Ure2p and Sup35p respectively. Ure2p and Sup35p, and now several other proteins, can form amyloid, a linear ordered polymer of protein monomers, with a part of each molecule, the prion domain, forming the core of this β-sheet structure. Amyloid filaments passed to a new cell seed the conversion of the normal form of the protein into the same amyloid form. The cell's phenotype is affected, usually from the deficiency of the normal form of the protein. Solid-state NMR studies indicate that the yeast prion amyloids are in-register parallel β-sheet structures, in which each residue (e.g. Asn35) forms a row along the filament long axis. The favourable interactions possible for aligned identical hydrophilic and hydrophobic residues are believed to be the mechanism for propagation of amyloid conformation. Thus, just as DNA mediates inheritance by templating its own sequence, these proteins act as genes by templating their conformation. Distinct isolates of a given prion have different biological properties, presumably determined by differences between the amyloid structures. Many lines of evidence indicate that the Saccharomyces cerevisiae prions are pathological disease agents, although the example of the [Het-s] prion of Podospora anserina shows that a prion can have beneficial aspects.

scholarly journals How Do Yeast Cells Contend with Prions?

2020 ◽  
Vol 21 (13) ◽  
pp. 4742 ◽  
Author(s):  
Reed B. Wickner ◽  
Herman K. Edskes ◽  
Moonil Son ◽  
Songsong Wu ◽  
Madaleine Niznikiewicz
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Prion Protein ◽  
Yeast Cells ◽  
Functional Amyloid ◽  
Inositol Polyphosphates ◽  
Yeast Prions ◽  
Amyloid Diseases ◽  
Infectious Proteins ◽  
Β Sheet

Infectious proteins (prions) include an array of human (mammalian) and yeast amyloid diseases in which a protein or peptide forms a linear β-sheet-rich filament, at least one functional amyloid prion, and two functional infectious proteins unrelated to amyloid. In Saccharomyces cerevisiae, at least eight anti-prion systems deal with pathogenic amyloid yeast prions by (1) blocking their generation (Ssb1,2, Ssz1, Zuo1), (2) curing most variants as they arise (Btn2, Cur1, Hsp104, Upf1,2,3, Siw14), and (3) limiting the pathogenicity of variants that do arise and propagate (Sis1, Lug1). Known mechanisms include facilitating proper folding of the prion protein (Ssb1,2, Ssz1, Zuo1), producing highly asymmetric segregation of prion filaments in mitosis (Btn2, Hsp104), competing with the amyloid filaments for prion protein monomers (Upf1,2,3), and regulation of levels of inositol polyphosphates (Siw14). It is hoped that the discovery of yeast anti-prion systems and elucidation of their mechanisms will facilitate finding analogous or homologous systems in humans, whose manipulation may be useful in treatment.

scholarly journals Anti-prion systems in yeast

2019 ◽  
Vol 294 (5) ◽  
pp. 1729-1738 ◽  
Author(s):  
Reed B. Wickner
Keyword(s):  
Mammalian Cells ◽  
Viral Infections ◽  
Podospora Anserina ◽  
Innate Immune ◽  
Large Majority ◽  
Yeast Cells ◽  
Immune Systems ◽  
Yeast Prions ◽  
Amyloid Diseases ◽  
Β Sheet

Yeast prions have become important models for the study of the basic mechanisms underlying human amyloid diseases. Yeast prions are pathogenic (unlike the [Het-s] prion of Podospora anserina), and most are amyloid-based with the same in-register parallel β-sheet architecture as most of the disease-causing human amyloids studied. Normal yeast cells eliminate the large majority of prion variants arising, and several anti-prion/anti-amyloid systems that eliminate them have been identified. It is likely that mammalian cells also have anti-amyloid systems, which may be useful in the same way humoral, cellular, and innate immune systems are used to treat or prevent bacterial and viral infections.

Insights into amyloid disease from fly models

2014 ◽  
Vol 56 ◽  
pp. 69-83 ◽  
Author(s):  
Ko-Fan Chen ◽  
Damian C. Crowther
Keyword(s):  
Drosophila Melanogaster ◽  
Neurodegenerative Disorders ◽  
Amyloid Β ◽  
Amyloid Β Peptide ◽  
Disease Pathogenesis ◽  
Amyloid Aggregates ◽  
Aβ Amyloid ◽  
Polypeptide Chains ◽  
Amyloid Diseases

The formation of amyloid aggregates is a feature of most, if not all, polypeptide chains. In vivo modelling of this process has been undertaken in the fruitfly Drosophila melanogaster with remarkable success. Models of both neurological and systemic amyloid diseases have been generated and have informed our understanding of disease pathogenesis in two main ways. First, the toxic amyloid species have been at least partially characterized, for example in the case of the Aβ (amyloid β-peptide) associated with Alzheimer's disease. Secondly, the genetic underpinning of model disease-linked phenotypes has been characterized for a number of neurodegenerative disorders. The current challenge is to integrate our understanding of disease-linked processes in the fly with our growing knowledge of human disease, for the benefit of patients.

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