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Regulation of Functional Protein Aggregation: From Amyloids to Biomaterials

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

Deadline for manuscript submissions: closed (30 June 2021) | Viewed by 19579

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Special Issue Editors

Prof. Dr. J.B. Bernd Helms

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Guest Editor

Department of Biomolecular Health Sciences, Utrecht University, Utrecht, The Netherlands
Interests: membrane transport; lipids; lipid droplets; lipidomics; liver fibrosis; liver regeneration; hepatic stellate cells; retinoids; functional amyloids; CAP superfamily proteins

Dr. Dora V. Kaloyanova

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Guest Editor

Department of Biomolecular Health Sciences, Utrecht University, Utrecht, The Netherlands
Interests: protein-protein interactions; protein aggregation; autophagy; reproduction

Dr. Stefan Rüdiger

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Guest Editor

Department of Chemistry, Utrecht University, Utrecht, The Netherlands
Interests: protein folding and Aggregation; Tau; heat shock proteins; chaperones

Special Issue Information

Dear Colleagues,

Numerous proteins and peptides have the capacity to self‐assemble into amyloid fibrils that are characterized by β-sheet polymer structures. Amyloid assembly has long been associated with many devastating human diseases, such as Alzheimer’s, Parkinson’s, diabetes type 2, and ALS.

Strikingly, amyloid folds with their remarkable, multifaceted appearance are also present in nature and occurring in various physiologically forms as so-called “functional amyloids”. They appear in fungi, insects, archaea, bacteria, and humans. Functional amyloids are often characterized by their reversible nature, unlike the extremely stable pathological amyloid fibrils. In addition, their presence requires careful biophysical control to avoid potentially harmful effects. This strongly suggests that functional amyloid assemblies are subject to strict regulation, leading to the formation of correct ‘sub’-structures to prevent toxicity and allowing reversal of amyloid assembly. Likewise, amyloid formation may be linked to liquid–liquid phase separation. The concept that is emerging is that amyloidic β-sheet folds can perform a multitude of biological functions. Rapid progress in the field of protein amyloid assembly now offers highly exciting new opportunities to unravel the secrets of amyloid formation. This will not only benefit the understanding of the role of functional and pathological amyloids in health and disease but will also promote innovation in bioengineering. The unique chemical characteristics of amyloidogenic proteins can be used to develop brand new materials for biofilm, biosensor, bioelectronic, and biomedical applications.

This Special Issue calls for original research in basic science and translational research, as well as for reviews and perspectives that address the existence, regulation, and role of functional amyloids in the physiology of organisms. In addition, contributions that describe progress to create new biomaterials based on β-sheet assemblies are welcomed.

Prof. Dr. J.B. Helms,

Dr. Dora V. Kaloyanova

Dr. Stefan Rüdiger

Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

Protein aggregation
β-sheet fold
Amyloids
Protein fibrils
Functional amyloids
Bioengineering
Biomaterials

Published Papers (6 papers)

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Research

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17 pages, 19418 KiB

Open AccessArticle

Global Proteotoxicity Caused by Human β₂ Microglobulin Variants Impairs the Unfolded Protein Response in C. elegans

by Sarah C. Good, Katherine M. Dewison, Sheena E. Radford and Patricija van Oosten-Hawle

Int. J. Mol. Sci. 2021, 22(19), 10752; https://doi.org/10.3390/ijms221910752 - 04 Oct 2021

Cited by 4 | Viewed by 2096

Abstract

Aggregation of β₂ microglobulin (β₂m) into amyloid fibrils is associated with systemic amyloidosis, caused by the deposition of amyloid fibrils containing the wild-type protein and its truncated variant, ΔN6 β₂m, in haemo-dialysed patients. A second form of familial systemic amyloidosis caused by the β₂m variant, D76N, results in amyloid deposits in the viscera, without renal dysfunction. Although the folding and misfolding mechanisms of β₂ microglobulin have been widely studied in vitro and in vivo, we lack a comparable understanding of the molecular mechanisms underlying toxicity in a cellular and organismal environment. Here, we established transgenic C. elegans lines expressing wild-type (WT) human β₂m, or the two highly amyloidogenic naturally occurring variants, D76N β₂m and ΔN6 β₂m, in the C. elegans bodywall muscle. Nematodes expressing the D76N β₂m and ΔN6 β₂m variants exhibit increased age-dependent and cell nonautonomous proteotoxicity associated with reduced motility, delayed development and shortened lifespan. Both β₂m variants cause widespread endogenous protein aggregation contributing to the increased toxicity in aged animals. We show that expression of β₂m reduces the capacity of C. elegans to cope with heat and endoplasmic reticulum (ER) stress, correlating with a deficiency to upregulate BiP/hsp-4 transcripts in response to ER stress in young adult animals. Interestingly, protein secretion in all β₂m variants is reduced, despite the presence of the natural signal sequence, suggesting a possible link between organismal β₂m toxicity and a disrupted ER secretory metabolism. Full article

(This article belongs to the Special Issue Regulation of Functional Protein Aggregation: From Amyloids to Biomaterials)

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14 pages, 4841 KiB

Open AccessArticle

Tyrp1 Mutant Variants Associated with OCA3: Computational Characterization of Protein Stability and Ligand Binding

by Milan H. Patel, Monika B. Dolinska and Yuri V. Sergeev

Int. J. Mol. Sci. 2021, 22(19), 10203; https://doi.org/10.3390/ijms221910203 - 22 Sep 2021

Cited by 5 | Viewed by 2015

Abstract

Oculocutaneous albinism type 3 (OCA3) is an autosomal recessive disorder caused by mutations in the TYRP1 gene. Tyrosinase-related protein 1 (Tyrp1) is involved in eumelanin synthesis, catalyzing the oxidation of 5,6-dihydroxyindole-2-carboxylic acid oxidase (DHICA) to 5,6-indolequinone-2-carboxylic acid (IQCA). Here, for the first time, four OCA3-causing mutations of Tyrp1, C30R, H215Y, D308N, and R326H, were investigated computationally to understand Tyrp1 protein stability and catalytic activity. Using the Tyrp1 crystal structure (PDB:5M8L), global mutagenesis was conducted to evaluate mutant protein stability. Consistent with the foldability parameter, C30R and H215Y should exhibit greater instability, and two other mutants, D308N and R326H, are expected to keep a native conformation. SDS-PAGE and Western blot analysis of the purified recombinant proteins confirmed that the foldability parameter correctly predicted the effect of mutations critical for protein stability. Further, the mutant variant structures were built and simulated for 100 ns to generate free energy landscapes and perform docking experiments. Free energy landscapes formed by Y362, N378, and T391 indicate that the binding clefts of C30R and H215Y mutants are larger than the wild-type Tyrp1. In docking simulations, the hydrogen bond and salt bridge interactions that stabilize DHICA in the active site remain similar among Tyrp1, D308N, and R326H. However, the strengths of these interactions and stability of the docked ligand may decrease proportionally to mutation severity due to the larger and less well-defined natures of the binding clefts in mutants. Mutational perturbations in mutants that are not unfolded may result in allosteric alterations to the active site, reducing the stability of protein-ligand interactions. Full article

(This article belongs to the Special Issue Regulation of Functional Protein Aggregation: From Amyloids to Biomaterials)

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17 pages, 17301 KiB

Open AccessArticle

Identification of Two Early Folding Stage Prion Non-Local Contacts Suggested to Serve as Key Steps in Directing the Final Fold to Be Either Native or Pathogenic

by Fernando Bergasa-Caceres and Herschel A. Rabitz

Int. J. Mol. Sci. 2021, 22(16), 8619; https://doi.org/10.3390/ijms22168619 - 10 Aug 2021

Cited by 2 | Viewed by 3431

Abstract

The initial steps of the folding pathway of the C-terminal domain of the murine prion protein mPrP(90–231) are predicted based on the sequential collapse model (SCM). A non-local dominant contact is found to form between the connecting region between helix 1 and β-sheet 1 and the C-terminal region of helix 3. This non-local contact nucleates the most populated molten globule-like intermediate along the folding pathway. A less stable early non-local contact between segments 120–124 and 179–183, located in the middle of helix 2, promotes the formation of a less populated molten globule-like intermediate. The formation of the dominant non-local contact constitutes an example of the postulated Nature’s Shortcut to the prion protein collapse into the native structure. The possible role of the less populated molten globule-like intermediate is explored as the potential initiation point for the folding for three pathogenic mutants (T182A, I214V, and Q211P in mouse prion numbering) of the prion protein. Full article

(This article belongs to the Special Issue Regulation of Functional Protein Aggregation: From Amyloids to Biomaterials)

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17 pages, 4489 KiB

Open AccessArticle

Biflavonoid-Induced Disruption of Hydrogen Bonds Leads to Amyloid-β Disaggregation

by Peter K. Windsor, Stephen P. Plassmeyer, Dominic S. Mattock, Jonathan C. Bradfield, Erika Y. Choi, Bill R. Miller III and Byung Hee Han

Int. J. Mol. Sci. 2021, 22(6), 2888; https://doi.org/10.3390/ijms22062888 - 12 Mar 2021

Cited by 21 | Viewed by 2620

Abstract

Deposition of amyloid β (Aβ) fibrils in the brain is a key pathologic hallmark of Alzheimer’s disease. A class of polyphenolic biflavonoids is known to have anti-amyloidogenic effects by inhibiting aggregation of Aβ and promoting disaggregation of Aβ fibrils. In the present study, we further sought to investigate the structural basis of the Aβ disaggregating activity of biflavonoids and their interactions at the atomic level. A thioflavin T (ThT) fluorescence assay revealed that amentoflavone-type biflavonoids promote disaggregation of Aβ fibrils with varying potency due to specific structural differences. The computational analysis herein provides the first atomistic details for the mechanism of Aβ disaggregation by biflavonoids. Molecular docking analysis showed that biflavonoids preferentially bind to the aromatic-rich, partially ordered N-termini of Aβ fibril via the π–π interactions. Moreover, docking scores correlate well with the ThT EC₅₀ values. Molecular dynamic simulations revealed that biflavonoids decrease the content of β-sheet in Aβ fibril in a structure-dependent manner. Hydrogen bond analysis further supported that the substitution of hydroxyl groups capable of hydrogen bond formation at two positions on the biflavonoid scaffold leads to significantly disaggregation of Aβ fibrils. Taken together, our data indicate that biflavonoids promote disaggregation of Aβ fibrils due to their ability to disrupt the fibril structure, suggesting biflavonoids as a lead class of compounds to develop a therapeutic agent for Alzheimer’s disease. Full article

(This article belongs to the Special Issue Regulation of Functional Protein Aggregation: From Amyloids to Biomaterials)

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Review

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16 pages, 2764 KiB

Open AccessReview

Viral Induced Protein Aggregation: A Mechanism of Immune Evasion

by Elena Muscolino, Laura-Marie Luoto and Wolfram Brune

Int. J. Mol. Sci. 2021, 22(17), 9624; https://doi.org/10.3390/ijms22179624 - 06 Sep 2021

Cited by 12 | Viewed by 5151

Abstract

Various intrinsic and extrinsic factors can interfere with the process of protein folding, resulting in protein aggregates. Usually, cells prevent the formation of aggregates or degrade them to prevent the cytotoxic effects they may cause. However, during viral infection, the formation of aggregates may serve as a cellular defense mechanism. On the other hand, some viruses are able to exploit the process of aggregate formation and removal to promote their replication or evade the immune response. This review article summarizes the process of cellular protein aggregation and gives examples of how different viruses exploit it. Particular emphasis is placed on the ribonucleotide reductases of herpesviruses and how their additional non-canonical functions in viral immune evasion are closely linked to protein aggregation. Full article

(This article belongs to the Special Issue Regulation of Functional Protein Aggregation: From Amyloids to Biomaterials)

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23 pages, 1570 KiB

Open AccessReview

Regulation of Functional Protein Aggregation by Multiple Factors: Implications for the Amyloidogenic Behavior of the CAP Superfamily Proteins

by Jie Sheng, Nick K. Olrichs, Bart M. Gadella, Dora V. Kaloyanova and J. Bernd Helms

Int. J. Mol. Sci. 2020, 21(18), 6530; https://doi.org/10.3390/ijms21186530 - 07 Sep 2020

Cited by 15 | Viewed by 3426

Abstract

The idea that amyloid fibrils and other types of protein aggregates are toxic for cells has been challenged by the discovery of a variety of functional aggregates. However, an identification of crucial differences between pathological and functional aggregation remains to be explored. Functional protein aggregation is often reversible by nature in order to respond properly to changing physiological conditions of the cell. In addition, increasing evidence indicates that fast fibril growth is a feature of functional amyloids, providing protection against the long-term existence of potentially toxic oligomeric intermediates. It is becoming clear that functional protein aggregation is a complexly organized process that can be mediated by a multitude of biomolecular factors. In this overview, we discuss the roles of diverse biomolecules, such as lipids/membranes, glycosaminoglycans, nucleic acids and metal ions, in regulating functional protein aggregation. Our studies on the protein GAPR-1 revealed that several of these factors influence the amyloidogenic properties of this protein. These observations suggest that GAPR-1, as well as the cysteine-rich secretory proteins, antigen 5 and pathogenesis-related proteins group 1 (CAP) superfamily of proteins that it belongs to, require the assembly into an amyloid state to exert several of their functions. A better understanding of functional aggregate formation may also help in the prevention and treatment of amyloid-related diseases. Full article

(This article belongs to the Special Issue Regulation of Functional Protein Aggregation: From Amyloids to Biomaterials)

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