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Life
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Biology of Protein Folding for Discovery of Novel Drugs
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Biology of Protein Folding for Discovery of Novel Drugs

A special issue of Life (ISSN 2075-1729). This special issue belongs to the section "Pharmaceutical Science".

Deadline for manuscript submissions: closed (25 January 2022) | Viewed by 33765

Special Issue Editors

Prof. Dr. Sung Jean Park

E-Mail Website
Guest Editor
College of Pharmacy, Gachon University, Incheon 21936, Republic of Korea
Interests: protein structure; drug discovery; protein folding; E3 ubiquitination; folding disease; protein degradation
Prof. Dr. Ji Woong Choi

E-Mail Website
Guest Editor
College of Pharmacy, Gachon University, Incheon 21936, Korea
Interests: neurodegenerative disease, multiple sclerosis, brain, stroke, neuropharmacology
Prof. Dr. Do-Hee Kim

E-Mail
Guest Editor
College of Pharmacy, Jeju National University, Jeju 63243, Korea
Interests: protein structure, protein folding, protein stability, interaction, drug screening

Special Issue Information

Dear Colleagues,

The problem in protein folding is one of the major concerns in modern biology. It is well known that misfolded protein aggregates provoke various human diseases including cancers, metabolic diseases, and neurodegenerative diseases. The structural quality and folding of proteins are tightly regulated in cells by so-called “quality control systems” including chaperones, ER responses, proteasomal degradation machinery, and autophagy. Though these areas have been extensively studied so far, there are still so many things unclear in terms of biophysics, molecular biology, cancer biology, and neurosciences. The basis of protein quality control should be helpful not only to understand the working mechanisms and pathogenic roles of proteins but also to discover and develop novel and new conceptual drugs. Moreover, targeting E3 ligases and autophagy system has become an attractive strategy for drug discovery. 

This Special Issue intends to present the latest advances in the field, covering protein structures related with folding, complexation, degradation, and biological discovery of related diseases. Biology of E3 ubiquitin ligase system and its application to drug discovery is also important concern. Original research, reviews, and short reports on basic biology, molecular mechanism of action, novel, or improved experimental approaches for studying folding issues, and novel drug discovery are welcomed.

Prof. Dr. Sung Jean Park
Prof. Dr. Ji Woong Choi
Prof. Dr. Do-Hee Kim
Guest Editors

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. Life is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). 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 structure and folding
  • Protein degradation
  • Degenerative disease
  • Folding disease
  • Drug discovery
  • E3 ubiquitin ligase
  • Amyloid
  • Chaperone

Published Papers (7 papers)

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Research

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13 pages, 2739 KiB  
Article
Recombinant Globular Domain of TcpA Pilin from Vibrio cholerae El Tor: Recovery from Inclusion Bodies and Structural Characterization
by Victor Marchenkov, Elena Dubovitskya, Nina Kotova, Igor Tuchkov, Nina Smirnova, Natalia Marchenko, Alexey Surin, Vladimir Filimonov and Gennady Semisotnov
Life 2022, 12(11), 1802; https://doi.org/10.3390/life12111802 - 07 Nov 2022
Viewed by 1172
Abstract
The production of recombinant proteins in Escherichia coli cells is often hampered by aggregation of newly synthesized proteins and formation of inclusion bodies. Here we propose the use of transverse urea gradient electrophoresis (TUGE) in testing the capability of folding of a recombinant [...] Read more.
The production of recombinant proteins in Escherichia coli cells is often hampered by aggregation of newly synthesized proteins and formation of inclusion bodies. Here we propose the use of transverse urea gradient electrophoresis (TUGE) in testing the capability of folding of a recombinant protein from inclusion bodies dissolved in urea. A plasmid encoding the amino acid sequence 55–224 of TcpA pilin (C-terminal globular domain: TcpA-C) from Vibrio cholerae El Tor enlarged by a His-tag on its N-terminus was expressed in E. coli cells. The major fraction (about 90%) of the target polypeptide was detected in cell debris. The polypeptide was isolated from the soluble fraction and recovered from inclusion bodies after their urea treatment. Some structural properties of the polypeptide from each sample proved identical. The refolding protocol was developed on the basis of TUGE data and successfully used for the protein large-scale recovery from inclusion bodies. Spectral, hydrodynamic, and thermodynamic characteristics of the recombinant TcpA recovered from inclusion bodies indicate the presence of a globular conformation with a pronounced secondary structure and a rigid tertiary structure, which is promising for the design of immunodiagnostics preparations aimed to assess the pilin level in different strains of V. cholerae and to develop cholera vaccines. Full article
(This article belongs to the Special Issue Biology of Protein Folding for Discovery of Novel Drugs)
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37 pages, 5870 KiB  
Article
The Link between Type 2 Diabetes Mellitus and the Polymorphisms of Glutathione-Metabolizing Genes Suggests a New Hypothesis Explaining Disease Initiation and Progression
by Iuliia Azarova, Elena Klyosova and Alexey Polonikov
Life 2021, 11(9), 886; https://doi.org/10.3390/life11090886 - 28 Aug 2021
Cited by 16 | Viewed by 7083
Abstract
The present study investigated whether type 2 diabetes (T2D) is associated with polymorphisms of genes encoding glutathione-metabolizing enzymes such as glutathione synthetase (GSS) and gamma-glutamyl transferase 7 (GGT7). A total of 3198 unrelated Russian subjects including 1572 T2D patients [...] Read more.
The present study investigated whether type 2 diabetes (T2D) is associated with polymorphisms of genes encoding glutathione-metabolizing enzymes such as glutathione synthetase (GSS) and gamma-glutamyl transferase 7 (GGT7). A total of 3198 unrelated Russian subjects including 1572 T2D patients and 1626 healthy subjects were enrolled. Single nucleotide polymorphisms (SNPs) of the GSS and GGT7 genes were genotyped using the MassArray-4 system. We found that the GSS and GGT7 gene polymorphisms alone and in combinations are associated with T2D risk regardless of sex, age, and body mass index, as well as correlated with plasma glutathione, hydrogen peroxide, and fasting blood glucose levels. Polymorphisms of GSS (rs13041792) and GGT7 (rs6119534 and rs11546155) genes were associated with the tissue-specific expression of genes involved in unfolded protein response and the regulation of proteostasis. Transcriptome-wide association analysis has shown that the pancreatic expression of some of these genes such as EDEM2, MYH7B, MAP1LC3A, and CPNE1 is linked to the genetic risk of T2D. A comprehensive analysis of the data allowed proposing a new hypothesis for the etiology of type 2 diabetes that endogenous glutathione deficiency might be a key condition responsible for the impaired folding of proinsulin which triggered an unfolded protein response, ultimately leading to beta-cell apoptosis and disease development. Full article
(This article belongs to the Special Issue Biology of Protein Folding for Discovery of Novel Drugs)
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Review

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14 pages, 2882 KiB  
Review
Structural Insights into Protein Regulation by Phosphorylation and Substrate Recognition of Protein Kinases/Phosphatases
by Seung-Hyeon Seok
Life 2021, 11(9), 957; https://doi.org/10.3390/life11090957 - 13 Sep 2021
Cited by 24 | Viewed by 8028
Abstract
Protein phosphorylation is one of the most widely observed and important post-translational modification (PTM) processes. Protein phosphorylation is regulated by protein kinases, each of which covalently attaches a phosphate group to an amino acid side chain on a serine (Ser), threonine (Thr), or [...] Read more.
Protein phosphorylation is one of the most widely observed and important post-translational modification (PTM) processes. Protein phosphorylation is regulated by protein kinases, each of which covalently attaches a phosphate group to an amino acid side chain on a serine (Ser), threonine (Thr), or tyrosine (Tyr) residue of a protein, and by protein phosphatases, each of which, conversely, removes a phosphate group from a phosphoprotein. These reversible enzyme activities provide a regulatory mechanism by activating or deactivating many diverse functions of proteins in various cellular processes. In this review, their structures and substrate recognition are described and summarized, focusing on Ser/Thr protein kinases and protein Ser/Thr phosphatases, and the regulation of protein structures by phosphorylation. The studies reviewed here and the resulting information could contribute to further structural, biochemical, and combined studies on the mechanisms of protein phosphorylation and to drug discovery approaches targeting protein kinases or protein phosphatases. Full article
(This article belongs to the Special Issue Biology of Protein Folding for Discovery of Novel Drugs)
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12 pages, 1206 KiB  
Review
The Role of Protein S-Nitrosylation in Protein Misfolding-Associated Diseases
by Yun-Jin Ju, Hye-Won Lee, Ji-Woong Choi and Min-Sik Choi
Life 2021, 11(7), 705; https://doi.org/10.3390/life11070705 - 17 Jul 2021
Cited by 8 | Viewed by 2899
Abstract
Abnormal and excessive nitrosative stress contributes to neurodegenerative disease associated with the production of pathological levels of misfolded proteins. The accumulated findings strongly suggest that excessive NO production can induce and deepen these pathological processes, particularly by the S-nitrosylation of target proteins. Therefore, [...] Read more.
Abnormal and excessive nitrosative stress contributes to neurodegenerative disease associated with the production of pathological levels of misfolded proteins. The accumulated findings strongly suggest that excessive NO production can induce and deepen these pathological processes, particularly by the S-nitrosylation of target proteins. Therefore, the relationship between S-nitrosylated proteins and the accumulation of misfolded proteins was reviewed. We particularly focused on the S-nitrosylation of E3-ubiquitin-protein ligase, parkin, and endoplasmic reticulum chaperone, PDI, which contribute to the accumulation of misfolded proteins. In addition to the target proteins being S-nitrosylated, NOS, which produces NO, and GSNOR, which inhibits S-nitrosylation, were also suggested as potential therapeutic targets for protein misfolding-associated diseases. Full article
(This article belongs to the Special Issue Biology of Protein Folding for Discovery of Novel Drugs)
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14 pages, 2013 KiB  
Review
Chemical-Mediated Targeted Protein Degradation in Neurodegenerative Diseases
by Soonsil Hyun and Dongyun Shin
Life 2021, 11(7), 607; https://doi.org/10.3390/life11070607 - 24 Jun 2021
Cited by 30 | Viewed by 8894
Abstract
Neurodegenerative diseases, including Alzheimer’s disease, Huntington’s disease, and Parkinson’s disease, are a class of diseases that lead to dysfunction of cognition and mobility. Aggregates of misfolded proteins such as β-amyloid, tau, α-synuclein, and polyglutamates are known to be among the main causes of [...] Read more.
Neurodegenerative diseases, including Alzheimer’s disease, Huntington’s disease, and Parkinson’s disease, are a class of diseases that lead to dysfunction of cognition and mobility. Aggregates of misfolded proteins such as β-amyloid, tau, α-synuclein, and polyglutamates are known to be among the main causes of neurodegenerative diseases; however, they are considered to be some of the most challenging drug targets because they cannot be modulated by conventional small-molecule agents. Recently, the degradation of target proteins by small molecules has emerged as a new therapeutic modality and has garnered the interest of the researchers in the pharmaceutical industry. Bifunctional molecules that recruit target proteins to a cellular protein degradation machinery, such as the ubiquitin–proteasome system and autophagy–lysosome pathway, have been designed. The representative targeted protein degradation technologies include molecular glues, proteolysis-targeting chimeras, hydrophobic tagging, autophagy-targeting chimeras, and autophagosome-tethering compounds. Although these modalities have been shown to degrade many disease-related proteins, such technologies are expected to be potentially important for neurogenerative diseases caused by protein aggregation. Herein, we review the recent progress in chemical-mediated targeted protein degradation toward the discovery of drugs for neurogenerative diseases. Full article
(This article belongs to the Special Issue Biology of Protein Folding for Discovery of Novel Drugs)
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17 pages, 1493 KiB  
Review
A Conceptual Framework for Integrating Cellular Protein Folding, Misfolding and Aggregation
by Seong Il Choi and Baik L. Seong
Life 2021, 11(7), 605; https://doi.org/10.3390/life11070605 - 24 Jun 2021
Cited by 4 | Viewed by 2332
Abstract
How proteins properly fold and maintain solubility at the risk of misfolding and aggregation in the cellular environments still remains largely unknown. Aggregation has been traditionally treated as a consequence of protein folding (or misfolding). Notably, however, aggregation can be generally inhibited by [...] Read more.
How proteins properly fold and maintain solubility at the risk of misfolding and aggregation in the cellular environments still remains largely unknown. Aggregation has been traditionally treated as a consequence of protein folding (or misfolding). Notably, however, aggregation can be generally inhibited by affecting the intermolecular interactions leading to aggregation, independently of protein folding and conformation. We here point out that rigorous distinction between protein folding and aggregation as two independent processes is necessary to reconcile and underlie all observations regarding the combined cellular protein folding and aggregation. So far, the direct attractive interactions (e.g., hydrophobic interactions) between cellular macromolecules including chaperones and interacting polypeptides have been widely believed to mainly stabilize polypeptides against aggregation. However, the intermolecular repulsions by large excluded volume and surface charges of cellular macromolecules can play a key role in stabilizing their physically connected polypeptides against aggregation, irrespective of the connection types and induced conformational changes, underlying the generic intrinsic chaperone activity of cellular macromolecules. Such rigorous distinction and intermolecular repulsive force-driven aggregation inhibition by cellular macromolecules could give new insights into understanding the complex cellular protein landscapes that remain uncharted. Full article
(This article belongs to the Special Issue Biology of Protein Folding for Discovery of Novel Drugs)
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8 pages, 1217 KiB  
Review
A Structural Approach into Drug Discovery Based on Autophagy
by Sung-Min Kang and Do-Hee Kim
Life 2021, 11(6), 526; https://doi.org/10.3390/life11060526 - 04 Jun 2021
Viewed by 2056
Abstract
Autophagy is a lysosome-dependent intracellular degradation machinery that plays an essential role in the regulation of cellular homeostasis. As many studies have revealed that autophagy is related to cancer, neurodegenerative diseases, metabolic diseases, and so on, and it is considered as a promising [...] Read more.
Autophagy is a lysosome-dependent intracellular degradation machinery that plays an essential role in the regulation of cellular homeostasis. As many studies have revealed that autophagy is related to cancer, neurodegenerative diseases, metabolic diseases, and so on, and it is considered as a promising drug target. Recent advances in structural determination and computational technologies provide important structural information on essential autophagy-related proteins. Combined with high-throughput screening methods, structure-activity relationship studies have led to the discovery of molecules that modulate autophagy. In this review, we summarize the recent structural studies on autophagy-related proteins and the discovery of modulators, indicating that targeting autophagy can be utilized as an effective strategy for novel drug development. Full article
(This article belongs to the Special Issue Biology of Protein Folding for Discovery of Novel Drugs)
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