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Protein Folding, Aggregation, and Cell Death

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A special issue of Biology (ISSN 2079-7737). This special issue belongs to the section "Cell Biology".

Deadline for manuscript submissions: closed (30 September 2021) | Viewed by 54256

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Special Issue Editors

Dr. Katsuya Iuchi

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Guest Editor

Department of Materials and Life Science, Faculty of Science and Technology, Seikei University, Tokyo 180-8633, Japan
Interests: cell death; apoptosis; necrosis; mitochondria; lipid peroxidation

Dr. Young-Ho Lee

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Guest Editor

Research Center for Bioconvergence Analysis, Korea Basic Science Institute, Ochang, Cheongju, Chungbuk 28199, Korea
Interests: protein misfolding and aggregation; protein structure/dynamics/stability; thermodynamics

Dr. Masaki Okumura

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Guest Editor

Frontier Research Institute for Interdisciplinary Sciences, Tohoku University, 6-3 Aramaki-Aza-Aoba, Aoba-ku, Sendai 980-8578, Japan
Interests: oxidative folding; chaperone; ER stress; protein homeostasis; LLPS

Special Issue Information

The protein homeostasis system, including autophagy, chaperone, and unfolded protein response, is one of the most essential gatekeepers to maintain cell homeostasis. Thus, the loss of protein homeostasis due to protein misfolding and aggregation often results in cell death with gain-of-toxic function and loss-of-function diseases such as neurodegenerative and many other aging-related disorders. Key and fundamental properties of protein (mis)folding and aggregation in causing cell death have been increasing revealed. However, a clearer understanding of the complex mechanisms of protein misfolding diseases remains elusive. This Special Issue focuses on in vitro and in vivo studies of protein folding, aggregation, and cell death.

Dear Colleagues,

Proteins are one of the most fundamental players for numerous biological processes that sustain living organisms. The correct folding of nascent polypeptides from unstructured conformations to the native structure in cells is a prerequisite for gain-of-function of proteins. Stochastic and environment-induced misfolding often results in irreversible protein aggregation, which causes loss-of-function and gain-of-toxic-function of proteins by damaging organelles and inducing cell death.

The protein homeostasis (proteostasis) system, including autophagy, unfolded protein response, and chaperone function, is fundamental to keep cell homeostasis. Among them, chaperone plays a central role for protein homeostasis by helping correct folding and preventing aggregation of misfolded proteins. Most seriously, errors in the proteostasis system in organelles, cells, tissues, and organs give rise to various protein misfolding diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), type 2 diabetes mellitus (T2DM), and amyotrophic lateral sclerosis (ALS). Misfolded and aggregated proteins interact with distinct cellular membranes, e.g., the plasma and organelle membranes, which affects the regulation of organelle function and intracellular signaling associated with apoptotic and non-apoptotic cell death processes. In addition, the interaction of mis-regulated protein aggregates with cellular organelles such as the mitochondria and endoplasmic reticulum has shown the loss of cellular calcium homeostasis with oxidative stress, thereby leading to several types of protein misfolding diseases.

Although several key and underlying aspects of protein folding, misfolding-induced aggregation, chaperone function, and their relation to cell death have been suggested, complicated linkages among these biological and pathological processes remain to be further discussed. In order to gain a deeper understanding, we invite cutting-edge researchers to submit original and review articles on the broad topic of “Protein Folding, Aggregation, and Cell Death”. This Special Issue will collect comprehensive manuscripts and provide valuable insight for the scientific community, ranging from basic to clinical researchers. Original research articles, timely reviews, and short communications are welcome.

Dr. Katsuya Iuchi

Dr. Young-Ho Lee

Dr. Masaki Okumura

Guest Editors

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Keywords

Amyloid fibril
Apoptotic cell death
Calcium homeostasis
Endoplasmic reticulum
Lipid membrane
Mitochondria
Non-apoptotic cell death
Organelle dysfunction
Oxidative stress
Protein aggregation
Protein folding
Protein misfolding disease

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Published Papers (13 papers)

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12 pages, 2088 KiB

Open AccessArticle

Computational Insights into the Unfolding of a Destabilized Superoxide Dismutase 1 Mutant

by Stepan Timr and Fabio Sterpone

Biology 2021, 10(12), 1240; https://doi.org/10.3390/biology10121240 - 27 Nov 2021

Cited by 2 | Viewed by 2215

Abstract

In this work, we investigate the

β

In this work, we investigate the

β

-barrel of superoxide dismutase 1 (SOD1) in a mutated form, the isoleucine 35 to alanine (I35A) mutant, commonly used as a model system to decipher the role of the full-length apoSOD1 protein in amyotrophic lateral sclerosis (ALS). It is known from experiments that the mutation reduces the stability of the SOD1 barrel and makes it largely unfolded in the cell at 37 degrees Celsius. We deploy state-of-the-art computational machinery to examine the thermal destabilization of the I35A mutant by comparing two widely used force fields, Amber a99SB-disp and CHARMM36m. We find that only the latter force field, when combined with the Replica Exchange with Solute Scaling (REST2) approach, reproduces semi-quantitatively the experimentally observed shift in the melting between the original and the mutated SOD1 barrel. In addition, we analyze the unfolding process and the conformational landscape of the mutant, finding these largely similar to those of the wildtype. Nevertheless, we detect an increased presence of partially misfolded states at ambient temperatures. These states, featuring conformational changes in the region of the

β

-strands

β

- β

6, might provide a pathway for nonnative aggregation. Full article

(This article belongs to the Special Issue Protein Folding, Aggregation, and Cell Death)

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22 pages, 5167 KiB

Open AccessArticle

Pathogenic D76N Variant of β₂-Microglobulin: Synergy of Diverse Effects in Both the Native and Amyloid States

by Éva Bulyáki, Judit Kun, Tamás Molnár, Alexandra Papp, András Micsonai, Henrietta Vadászi, Borbála Márialigeti, Attila István Kovács, Gabriella Gellén, Keiichi Yamaguchi, Yuxi Lin, Masatomo So, Mihály Józsi, Gitta Schlosser, Young-Ho Lee, Károly Liliom, Yuji Goto and József Kardos

Biology 2021, 10(11), 1197; https://doi.org/10.3390/biology10111197 - 17 Nov 2021

Cited by 3 | Viewed by 2932

Abstract

β₂-microglobulin (β2m), the light chain of the MHC-I complex, is associated with dialysis-related amyloidosis (DRA). Recently, a hereditary systemic amyloidosis was discovered, caused by a naturally occurring D76N β2m variant, which showed a structure remarkably similar to the wild-type (WT) protein, albeit with decreased thermodynamic stability and increased amyloidogenicity. Here, we investigated the role of the D76N mutation in the amyloid formation of β2m by point mutations affecting the Asp76-Lys41 ion-pair of WT β2m and the charge cluster on Asp38. Using a variety of biophysical techniques, we investigated the conformational stability and partial unfolding of the native state of the variants, as well as their amyloidogenic propensity and the stability of amyloid fibrils under various conditions. Furthermore, we studied the intermolecular interactions of WT and mutant proteins with various binding partners that might have in vivo relevance. We found that, relative to WT β2m, the exceptional amyloidogenicity of the pathogenic D76N β2m variant is realized by the deleterious synergy of diverse effects of destabilized native structure, higher sensitivity to negatively charged amphiphilic molecules (e.g., lipids) and polyphosphate, more effective fibril nucleation, higher conformational stability of fibrils, and elevated affinity for extracellular components, including extracellular matrix proteins. Full article

(This article belongs to the Special Issue Protein Folding, Aggregation, and Cell Death)

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13 pages, 2336 KiB

Open AccessArticle

Molecular Effects of Elongation Factor Ts and Trigger Factor on the Unfolding and Aggregation of Elongation Factor Tu Induced by the Prokaryotic Molecular Chaperone Hsp33

by Minho Keum, Dai Ito, Mi-Seong Kim, Yuxi Lin, Kyeong-Hyeon Yoon, Jihoon Kim, Sung-Hee Lee, Ji-Hun Kim, Wookyung Yu, Young-Ho Lee and Hyung-Sik Won

Biology 2021, 10(11), 1171; https://doi.org/10.3390/biology10111171 - 12 Nov 2021

Cited by 3 | Viewed by 2926

Abstract

Hsp33, a prokaryotic redox-regulated holding chaperone, has been recently identified to be able to exhibit an unfoldase and aggregase activity against elongation factor Tu (EF-Tu) in its reduced state. In this study, we investigated the effect of elongation factor Ts (EF-Ts) and trigger factor (TF) on Hsp33-mediated EF-Tu unfolding and aggregation using gel filtration, light scattering, circular dichroism, and isothermal titration calorimetry. We found that EF-Tu unfolding and subsequent aggregation induced by Hsp33 were evident even in its complex state with EF-Ts, which enhanced EF-Tu stability. In addition, although TF alone had no substantial effect on the stability of EF-Tu, it markedly amplified the Hsp33-mediated EF-Tu unfolding and aggregation. Collectively, the present results constitute the first example of synergistic unfoldase/aggregase activity of molecular chaperones and suggest that the stability of EF-Tu is modulated by a sophisticated network of molecular chaperones to regulate protein biosynthesis in cells under stress conditions. Full article

(This article belongs to the Special Issue Protein Folding, Aggregation, and Cell Death)

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15 pages, 2179 KiB

Open AccessArticle

Functional Interplay between P5 and PDI/ERp72 to Drive Protein Folding

by Motonori Matsusaki, Rina Okada, Yuya Tanikawa, Shingo Kanemura, Dai Ito, Yuxi Lin, Mai Watabe, Hiroshi Yamaguchi, Tomohide Saio, Young-Ho Lee, Kenji Inaba and Masaki Okumura

Biology 2021, 10(11), 1112; https://doi.org/10.3390/biology10111112 - 28 Oct 2021

Cited by 4 | Viewed by 3513

Abstract

P5 is one of protein disulfide isomerase family proteins (PDIs) involved in endoplasmic reticulum (ER) protein quality control that assists oxidative folding, inhibits protein aggregation, and regulates the unfolded protein response. P5 reportedly interacts with other PDIs via intermolecular disulfide bonds in cultured cells, but it remains unclear whether complex formation between P5 and other PDIs is involved in regulating enzymatic and chaperone functions. Herein, we established the far-western blot method to detect non-covalent interactions between P5 and other PDIs and found that PDI and ERp72 are partner proteins of P5. The enzymatic activity of P5-mediated oxidative folding is up-regulated by PDI, while the chaperone activity of P5 is stimulated by ERp72. These findings shed light on the mechanism by which the complex formations among PDIs drive to synergistically accelerate protein folding and prevents aggregation. This knowledge has implications for understanding misfolding-related pathology. Full article

(This article belongs to the Special Issue Protein Folding, Aggregation, and Cell Death)

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13 pages, 1787 KiB

Open AccessArticle

Zinc-Dependent Oligomerization of Thermus thermophilus Trigger Factor Chaperone

by Haojie Zhu, Motonori Matsusaki, Taiga Sugawara, Koichiro Ishimori and Tomohide Saio

Biology 2021, 10(11), 1106; https://doi.org/10.3390/biology10111106 - 26 Oct 2021

Cited by 3 | Viewed by 2699

Abstract

Thermus thermophilus trigger factor (TtTF) is a zinc-dependent molecular chaperone whose folding-arrest activity is regulated by Zn²⁺. However, little is known about the mechanism of zinc-dependent regulation of the TtTF activity. Here we exploit in vitro biophysical experiments to investigate zinc-binding, the oligomeric state, the secondary structure, and the thermal stability of TtTF in the absence and presence of Zn²⁺. The data show that full-length TtTF binds Zn²⁺, but the isolated domains and tandem domains of TtTF do not bind to Zn²⁺. Furthermore, circular dichroism (CD) and nuclear magnetic resonance (NMR) spectra suggested that Zn²⁺-binding induces the partial structural changes of TtTF, and size exclusion chromatography-multi-angle light scattering (SEC-MALS) showed that Zn²⁺ promotes TtTF oligomerization. Given the previous work showing that the activity regulation of E. coli trigger factor is accompanied by oligomerization, the data suggest that TtTF exploits zinc ions to induce the structural change coupled with the oligomerization to assemble the client-binding site, thereby effectively preventing proteins from misfolding in the thermal environment. Full article

(This article belongs to the Special Issue Protein Folding, Aggregation, and Cell Death)

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14 pages, 3947 KiB

Open AccessArticle

Abnormal Enhancement of Protein Disulfide Isomerase-like Activity of a Cyclic Diselenide Conjugated with a Basic Amino Acid by Inserting a Glycine Spacer

by Rumi Mikami, Shunsuke Tsukagoshi and Kenta Arai

Biology 2021, 10(11), 1090; https://doi.org/10.3390/biology10111090 - 24 Oct 2021

Cited by 3 | Viewed by 2517

Abstract

In a previous study, we reported that (S)-1,2-diselenane-4-amine (1) catalyzes oxidative protein folding through protein disulfide isomerase (PDI)-like catalytic mechanisms and that the direct conjugation of a basic amino acid (Xaa: His, Lys, or Arg) via an amide bond improves the catalytic activity of 1 by increasing its diselenide (Se–Se) reduction potential (E′°). In this study, to modulate the Se–Se redox properties and the association of the compounds with a protein substrate, new catalysts, in which a Gly spacer was inserted between 1 and Xaa, were synthesized. Exhaustive comparison of the PDI-like catalytic activities and E′° values among 1, 1-Xaa, and 1-Gly-Xaa showed that the insertion of a Gly spacer into 1-Xaa either did not change or slightly reduced the PDI-like activity and the E′° values. Importantly, however, only 1-Gly-Arg deviated from this generality and showed obviously increased E°′ value and PDI-like activity compared to the corresponding compound with no Gly spacer (1-Arg); on the contrary, its catalytic activity was the highest among the diselenide compounds employed in this study, while this abnormal enhancement of the catalytic activity of 1-Gly-Arg could not be fully explained by the thermodynamics of the Se–Se bond and its association ability with protein substrates. Full article

(This article belongs to the Special Issue Protein Folding, Aggregation, and Cell Death)

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13 pages, 4354 KiB

Open AccessArticle

Idebenone Decreases Aβ Pathology by Modulating RAGE/Caspase-3 Signaling and the Aβ Degradation Enzyme NEP in a Mouse Model of AD

by Hyun-ju Lee, Ha-Ram Jeong, Jin-Hee Park and Hyang-Sook Hoe

Biology 2021, 10(9), 938; https://doi.org/10.3390/biology10090938 - 19 Sep 2021

Cited by 15 | Viewed by 3613

Abstract

The coenzyme Q10 analogue idebenone is an FDA-approved antioxidant that can cross the blood–brain barrier (BBB). The effects of idebenone on the pathology of Alzheimer’s disease (AD) and the underlying molecular mechanisms have not been comprehensively investigated. Here, we examined the impact of idebenone treatment on AD pathology in 5xFAD mice, a model of AD. Idebenone significantly downregulated Aβ plaque number via multi-directional pathways in this model. Specifically, idebenone reduced the RAGE/caspase-3 signaling pathway and increased levels of the Aβ degradation enzyme NEP and α-secretase ADAM17 in 5xFAD mice. Importantly, idebenone significantly suppressed tau kinase p-GSK3β^Y216 levels, thereby inhibiting tau hyperphosphorylation at Thr231 and total tau levels in 5xFAD mice. Taken together, the present study indicates that idebenone modulates amyloidopathy and tauopathy in 5xFAD mice, suggesting therapeutic potential for AD. Full article

(This article belongs to the Special Issue Protein Folding, Aggregation, and Cell Death)

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13 pages, 1737 KiB

Open AccessArticle

The Function of Drosophila USP14 in Endoplasmic Reticulum Stress and Retinal Degeneration in a Model for Autosomal Dominant Retinitis Pigmentosa

by Jung-Eun Park, Thị Xuân Thùy Trần, Nayoung Park, Jeonghun Yeom, Kyunggon Kim and Min-Ji Kang

Biology 2020, 9(10), 332; https://doi.org/10.3390/biology9100332 - 12 Oct 2020

Cited by 4 | Viewed by 3807

Abstract

Endoplasmic reticulum (ER) stress and its adaptive cellular response, the unfolded protein response (UPR), are involved in various diseases including neurodegenerative diseases, metabolic diseases, and even cancers. Here, we analyzed the novel function of ubiquitin-specific peptidase 14 (USP14) in ER stress. The overexpression of Drosophila USP14 protected the cells from ER stress without affecting the proteasomal activity. Null Hong Kong (NHK) and alpha-1-antitrypsin Z (ATZ) are ER-associated degradation substrates. The degradation of NHK, but not of ATZ, was delayed by USP14. USP14 restored the levels of rhodopsin-1 protein in a Drosophila model for autosomal dominant retinitis pigmentosa and suppressed the retinal degeneration in this model. In addition, we observed that proteasome complex is dynamically reorganized in response to ER stress in human 293T cells. These findings suggest that USP14 may be a therapeutic strategy in diseases associated with ER stress. Full article

(This article belongs to the Special Issue Protein Folding, Aggregation, and Cell Death)

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Review

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16 pages, 1271 KiB

Open AccessReview

Oligomannose-Type Glycan Processing in the Endoplasmic Reticulum and Its Importance in Misfolding Diseases

by Taiki Kuribara and Kiichiro Totani

Biology 2022, 11(2), 199; https://doi.org/10.3390/biology11020199 - 27 Jan 2022

Cited by 7 | Viewed by 3826

Abstract

Glycoprotein folding plays a critical role in sorting glycoprotein secretion and degradation in the endoplasmic reticulum (ER). Furthermore, relationships between glycoprotein folding and several diseases, such as type 2 diabetes and various neurodegenerative disorders, are indicated. Patients’ cells with type 2 diabetes, and various neurodegenerative disorders induce ER stress, against which the cells utilize the unfolded protein response for protection. However, in some cases, chronic and/or massive ER stress causes critical damage to cells, leading to the onset of ER stress-related diseases, which are categorized into misfolding diseases. Accumulation of misfolded proteins may be a cause of ER stress, in this respect, perturbation of oligomannose-type glycan processing in the ER may occur. A great number of studies indicate the relationships between ER stress and misfolding diseases, while little evidence has been reported on the connection between oligomannose-type glycan processing and misfolding diseases. In this review, we summarize alteration of oligomannose-type glycan processing in several ER stress-related diseases, especially misfolding diseases and show the possibility of these alteration of oligomannose-type glycan processing as indicators of diseases. Full article

(This article belongs to the Special Issue Protein Folding, Aggregation, and Cell Death)

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15 pages, 1696 KiB

Open AccessReview

Association between Sleep, Alzheimer’s, and Parkinson’s Disease

by Sumire Matsumoto and Tomomi Tsunematsu

Biology 2021, 10(11), 1127; https://doi.org/10.3390/biology10111127 - 3 Nov 2021

Cited by 26 | Viewed by 5661

Abstract

The majority of neurodegenerative diseases are pathologically associated with protein misfolding and aggregation. Alzheimer’s disease (AD) is a type of dementia that slowly affects memory and cognitive function, and is characterized by the aggregation of the β-amyloid protein and tau neurofibrillary tangles in the brain. Parkinson’s disease (PD) is a movement disorder typically resulting in rigidity and tremor, which is pathologically linked to the aggregation of α-synuclein, particularly in dopaminergic neurons in the midbrain. Sleep disorders commonly occur in AD and PD patients, and it can precede the onset of these diseases. For example, cognitively normal older individuals who have highly fragmented sleep had a 1.5-fold increased risk of subsequently developing AD. This suggests that sleep abnormalities may be a potential biomarker of these diseases. In this review, we describe the alterations of sleep in AD and PD, and discuss their potential in the early diagnosis of these diseases. We further discuss whether sleep disturbance could be a target for the treatment of these diseases. Full article

(This article belongs to the Special Issue Protein Folding, Aggregation, and Cell Death)

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11 pages, 1563 KiB

Open AccessReview

¹⁷O NMR Spectroscopy: A Novel Probe for Characterizing Protein Structure and Folding

by Srinivasan Muniyappan, Yuxi Lin, Young-Ho Lee and Jin Hae Kim

Biology 2021, 10(6), 453; https://doi.org/10.3390/biology10060453 - 21 May 2021

Cited by 13 | Viewed by 4110

Abstract

Oxygen is a key atom that maintains biomolecular structures, regulates various physiological processes, and mediates various biomolecular interactions. Oxygen-17 (¹⁷O), therefore, has been proposed as a useful probe that can provide detailed information about various physicochemical features of proteins. This is attributed to the facts that (1) ¹⁷O is an active isotope for nuclear magnetic resonance (NMR) spectroscopic approaches; (2) NMR spectroscopy is one of the most suitable tools for characterizing the structural and dynamical features of biomolecules under native-like conditions; and (3) oxygen atoms are frequently involved in essential hydrogen bonds for the structural and functional integrity of proteins or related biomolecules. Although ¹⁷O NMR spectroscopic investigations of biomolecules have been considerably hampered due to low natural abundance and the quadruple characteristics of the ¹⁷O nucleus, recent theoretical and technical developments have revolutionized this methodology to be optimally poised as a unique and widely applicable tool for determining protein structure and dynamics. In this review, we recapitulate recent developments in ¹⁷O NMR spectroscopy to characterize protein structure and folding. In addition, we discuss the highly promising advantages of this methodology over other techniques and explain why further technical and experimental advancements are highly desired. Full article

(This article belongs to the Special Issue Protein Folding, Aggregation, and Cell Death)

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19 pages, 1876 KiB

Open AccessReview

Cell Death via Lipid Peroxidation and Protein Aggregation Diseases

by Katsuya Iuchi, Tomoka Takai and Hisashi Hisatomi

Biology 2021, 10(5), 399; https://doi.org/10.3390/biology10050399 - 4 May 2021

Cited by 27 | Viewed by 9332

Abstract

Lipid peroxidation of cellular membranes is a complicated cellular event, and it is both the cause and result of various diseases, such as ischemia-reperfusion injury, neurodegenerative diseases, and atherosclerosis. Lipid peroxidation causes non-apoptotic cell death, which is associated with cell fate determination: survival or cell death. During the radical chain reaction of lipid peroxidation, various oxidized lipid products accumulate in cells, followed by organelle dysfunction and the induction of non-apoptotic cell death. Highly reactive oxidized products from unsaturated fatty acids are detected under pathological conditions. Pathological protein aggregation is the general cause of these diseases. The cellular response to misfolded proteins is well-known as the unfolded protein response (UPR) and it is partially concomitant with the response to lipid peroxidation. Moreover, the association between protein aggregation and non-apoptotic cell death by lipid peroxidation is attracting attention. The link between lipid peroxidation and protein aggregation is a matter of concern in biomedical fields. Here, we focus on lethal protein aggregation in non-apoptotic cell death via lipid peroxidation. We reviewed the roles of protein aggregation in the initiation and execution of non-apoptotic cell death. We also considered the relationship between protein aggregation and oxidized lipid production. We provide an overview of non-apoptotic cell death with a focus on lipid peroxidation for therapeutic targeting during protein aggregation diseases. Full article

(This article belongs to the Special Issue Protein Folding, Aggregation, and Cell Death)

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28 pages, 987 KiB

Open AccessReview

Amyloids: The History of Toxicity and Functionality

by Elmira I. Yakupova, Liya G. Bobyleva, Sergey A. Shumeyko, Ivan M. Vikhlyantsev and Alexander G. Bobylev

Biology 2021, 10(5), 394; https://doi.org/10.3390/biology10050394 - 1 May 2021

Cited by 22 | Viewed by 4235

Abstract

Proteins can perform their specific function due to their molecular structure. Partial or complete unfolding of the polypeptide chain may lead to the misfolding and aggregation of proteins in turn, resulting in the formation of different structures such as amyloid aggregates. Amyloids are rigid protein aggregates with the cross-β structure, resistant to most solvents and proteases. Because of their resistance to proteolysis, amyloid aggregates formed in the organism accumulate in tissues, promoting the development of various diseases called amyloidosis, for instance Alzheimer’s diseases (AD). According to the main hypothesis, it is considered that the cause of AD is the formation and accumulation of amyloid plaques of Aβ. That is why Aβ-amyloid is the most studied representative of amyloids. Therefore, in this review, special attention is paid to the history of Aβ-amyloid toxicity. We note the main problems with anti-amyloid therapy and write about new views on amyloids that can play positive roles in the different organisms including humans. Full article

(This article belongs to the Special Issue Protein Folding, Aggregation, and Cell Death)

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