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Infection Apr 2021The coronavirus outbreak emerged as a severe pandemic, claiming more than 0.8 million lives across the world and raised a major global health concern. We survey the...
PURPOSE
The coronavirus outbreak emerged as a severe pandemic, claiming more than 0.8 million lives across the world and raised a major global health concern. We survey the history and mechanism of coronaviruses, and the structural characteristics of the spike protein and its key residues responsible for human transmissions.
METHODS
We have carried out a systematic review to summarize the origin, transmission and etiology of COVID-19. The structural analysis of the spike protein and its disordered residues explains the mechanism of the viral transmission. A meta-data analysis of the therapeutic compounds targeting the SARS-CoV-2 is also included.
RESULTS
Coronaviruses can cross the species barrier and infect humans with unexpected consequences for public health. The transmission rate of SARS-CoV-2 infection is higher compared to that of the closely related SARS-CoV infections. In SARS-CoV-2 infection, intrinsically disordered regions are observed at the interface of the spike protein and ACE2 receptor, providing a shape complementarity to the complex. The key residues of the spike protein have stronger binding affinity with ACE2. These can be probable reasons for the higher transmission rate of SARS-CoV-2. In addition, we have also discussed the therapeutic compounds and the vaccines to target SARS-CoV-2, which can help researchers to develop effective drugs/vaccines for COVID-19. The overall history and mechanism of entry of SARS-CoV-2 along with structural study of spike-ACE2 complex provide insights to understand disease pathogenesis and development of vaccines and drugs.
Topics: Amino Acid Sequence; Animals; COVID-19; Coronavirus Infections; Humans; Protein Binding; Protein Folding; SARS-CoV-2; Spike Glycoprotein, Coronavirus; Virus Internalization; COVID-19 Drug Treatment
PubMed: 32886331
DOI: 10.1007/s15010-020-01516-2 -
Journal of Assisted Reproduction and... Jun 2023The storage and release of calcium ions (Ca2 +) in oocyte maturation and fertilization are particularly noteworthy features of the endoplasmic reticulum (ER). The ER... (Review)
Review
The storage and release of calcium ions (Ca2 +) in oocyte maturation and fertilization are particularly noteworthy features of the endoplasmic reticulum (ER). The ER is the largest organelle in the cell composed of rough ER, smooth ER, and nuclear envelope, and is the main site of protein synthesis, transport and folding, and lipid and steroid synthesis. An appropriate calcium signaling response can initiate oocyte development and embryogenesis, and the ER is the central link that initiates calcium signaling. The transition from immature oocytes to zygotes also requires many coordinated organelle reorganizations and changes. Therefore, the purpose of this review is to generalize information on the function, structure, interaction with other organelles, and spatiotemporal localization of the ER in mammalian oocytes. Mechanisms related to maintaining ER homeostasis have been extensively studied in recent years. Resolving ER stress through the unfolded protein response (UPR) is one of them. We combined the clinical problems caused by the ER in in vitro maturation (IVM), and the mechanisms of ER have been identified by single-cell RNA-seq. This article systematically reviews the functions of ER and provides a reference for assisted reproductive technology (ART) research.
Topics: Animals; Oocytes; Unfolded Protein Response; Endoplasmic Reticulum Stress; Oogenesis; Endoplasmic Reticulum; Mammals
PubMed: 37171741
DOI: 10.1007/s10815-023-02782-3 -
Frontiers in Bioengineering and... 2022Proteins are some of the most fascinating and challenging molecules in the universe, and they pose a big challenge for artificial intelligence. The implementation of...
Proteins are some of the most fascinating and challenging molecules in the universe, and they pose a big challenge for artificial intelligence. The implementation of machine learning/AI in protein science gives rise to a world of knowledge adventures in the workhorse of the cell and proteome homeostasis, which are essential for making life possible. This opens up epistemic horizons thanks to a coupling of human tacit-explicit knowledge with machine learning power, the benefits of which are already tangible, such as important advances in protein structure prediction. Moreover, the driving force behind the protein processes of self-organization, adjustment, and fitness requires a space corresponding to gigabytes of life data in its order of magnitude. There are many tasks such as novel protein design, protein folding pathways, and synthetic metabolic routes, as well as protein-aggregation mechanisms, pathogenesis of protein misfolding and disease, and proteostasis networks that are currently unexplored or unrevealed. In this systematic review and biochemical meta-analysis, we aim to contribute to bridging the gap between what we call artificial intelligence (AI) and protein science (PS), a growing research enterprise with exciting and promising biotechnological and biomedical applications. We undertake our task by exploring "the state of the art" in AI and machine learning (ML) applications to protein science in the scientific literature to address some critical research questions in this domain, including What kind of tasks are already explored by ML approaches to protein sciences? What are the most common ML algorithms and databases used? What is the situational diagnostic of the AI-PS inter-field? What do ML processing steps have in common? We also formulate novel questions such as Is it possible to discover what the rules of protein evolution are with the binomial AI-PS? How do protein folding pathways evolve? What are the rules that dictate the folds? What are the minimal nuclear protein structures? How do protein aggregates form and why do they exhibit different toxicities? What are the structural properties of amyloid proteins? How can we design an effective proteostasis network to deal with misfolded proteins? We are a cross-functional group of scientists from several academic disciplines, and we have conducted the systematic review using a variant of the PICO and PRISMA approaches. The search was carried out in four databases (PubMed, Bireme, OVID, and EBSCO Web of Science), resulting in 144 research articles. After three rounds of quality screening, 93 articles were finally selected for further analysis. A summary of our findings is as follows: regarding AI applications, there are mainly four types: ) genomics, ) protein structure and function, ) protein design and evolution, and ) drug design. In terms of the ML algorithms and databases used, supervised learning was the most common approach (85%). As for the databases used for the ML models, PDB and UniprotKB/Swissprot were the most common ones (21 and 8%, respectively). Moreover, we identified that approximately 63% of the articles organized their results into three steps, which we labeled , , and . A few studies combined data from several databases or created their own databases after the pre-process. Our main finding is that, as of today, there are no research road maps serving as guides to address gaps in our knowledge of the AI-PS binomial. All research efforts to collect, integrate multidimensional data features, and then analyze and validate them are, so far, uncoordinated and scattered throughout the scientific literature without a clear epistemic goal or connection between the studies. Therefore, our main contribution to the scientific literature is to offer a road map to help solve problems in drug design, protein structures, design, and function prediction while also presenting the "state of the art" on research in the AI-PS binomial until February 2021. Thus, we pave the way toward future advances in the synthetic redesign of novel proteins and protein networks and artificial metabolic pathways, learning lessons from nature for the welfare of humankind. Many of the novel proteins and metabolic pathways are currently non-existent in nature, nor are they used in the chemical industry or biomedical field.
PubMed: 35875501
DOI: 10.3389/fbioe.2022.788300 -
Frontiers in Physiology 2020This review summarizes the current evidence for the involvement of proteotoxicity and protein quality control systems defects in diseases of the central nervous and...
This review summarizes the current evidence for the involvement of proteotoxicity and protein quality control systems defects in diseases of the central nervous and cardiovascular systems. Specifically, it presents the commonalities between the pathophysiology of protein misfolding diseases in the heart and the brain. The involvement of protein homeostasis dysfunction has been for long time investigated and accepted as one of the leading pathophysiological causes of neurodegenerative diseases. In cardiovascular diseases instead the mechanistic focus had been on the primary role of Ca dishomeostasis, myofilament dysfunction as well as extracellular fibrosis, whereas no attention was given to misfolding of proteins as a pathogenetic mechanism. Instead, in the recent years, several contributions have shown protein aggregates in failing hearts similar to the ones found in the brain and increasing evidence have highlighted the crucial importance that proteotoxicity exerts via pre-amyloidogenic species in cardiovascular diseases as well as the prominent role of the cellular response to misfolded protein accumulation. As a result, proteotoxicity, unfolding protein response (UPR), and ubiquitin-proteasome system (UPS) have recently been investigated as potential key pathogenic pathways and therapeutic targets for heart disease. Overall, the current knowledge summarized in this review describes how the misfolding process in the brain parallels in the heart. Understanding the folding and unfolding mechanisms involved early through studies in the heart will provide new knowledge for neurodegenerative proteinopathies and may prepare the stage for targeted and personalized interventions.
PubMed: 33584340
DOI: 10.3389/fphys.2020.625974 -
Molecular Medicine (Cambridge, Mass.) Aug 2023Glucose-Regulated Protein 78 (GRP78) is a chaperone protein that is predominantly expressed in the lumen of the endoplasmic reticulum. GRP78 plays a crucial role in... (Review)
Review
Glucose-Regulated Protein 78 (GRP78) is a chaperone protein that is predominantly expressed in the lumen of the endoplasmic reticulum. GRP78 plays a crucial role in protein folding by assisting in the assembly of misfolded proteins. Under cellular stress conditions, GRP78 can translocate to the cell surface (csGRP78) were it interacts with different ligands to initiate various intracellular pathways. The expression of csGRP78 has been associated with tumor initiation and progression of multiple cancer types. This review provides a comprehensive analysis of the existing evidence on the roles of GRP78 in various types of cancer and other human pathology. Additionally, the review discusses the current understanding of the mechanisms underlying GRP78's involvement in tumorigenesis and cancer advancement. Furthermore, we highlight recent innovative approaches employed in downregulating GRP78 expression in cancers as a potential therapeutic target.
Topics: Humans; Endoplasmic Reticulum Chaperone BiP; Neoplasms; Cell Transformation, Neoplastic; Endoplasmic Reticulum
PubMed: 37605113
DOI: 10.1186/s10020-023-00706-6 -
Current Obesity Reports May 2024The present study aims to review the existing literature to identify pathophysiological proteins in obesity by conducting a systematic review of proteomics studies.... (Review)
Review
PURPOSE OF REVIEW
The present study aims to review the existing literature to identify pathophysiological proteins in obesity by conducting a systematic review of proteomics studies. Proteomics may reveal the mechanisms of obesity development and clarify the links between obesity and related diseases, improving our comprehension of obesity and its clinical implications.
RECENT FINDINGS
Most of the molecular events implicated in obesity development remain incomplete. Proteomics stands as a powerful tool for elucidating the intricate interactions among proteins in the context of obesity. This methodology has the potential to identify proteins involved in pathological processes and to evaluate changes in protein abundance during obesity development, contributing to the identification of early disease predisposition, monitoring the effectiveness of interventions and improving disease management overall. Despite many non-targeted proteomic studies exploring obesity, a comprehensive and up-to-date systematic review of the molecular events implicated in obesity development is lacking. The lack of such a review presents a significant challenge for researchers trying to interpret the existing literature. This systematic review was conducted following the PRISMA guidelines and included sixteen human proteomic studies, each of which delineated proteins exhibiting significant alterations in obesity. A total of 41 proteins were reported to be altered in obesity by at least two or more studies. These proteins were involved in metabolic pathways, oxidative stress responses, inflammatory processes, protein folding, coagulation, as well as structure/cytoskeleton. Many of the identified proteomic biomarkers of obesity have also been reported to be dysregulated in obesity-related disease. Among them, seven proteins, which belong to metabolic pathways (aldehyde dehydrogenase and apolipoprotein A1), the chaperone family (albumin, heat shock protein beta 1, protein disulfide-isomerase A3) and oxidative stress and inflammation proteins (catalase and complement C3), could potentially serve as biomarkers for the progression of obesity and the development of comorbidities, contributing to personalized medicine in the field of obesity. Our systematic review in proteomics represents a substantial step forward in unravelling the complexities of protein alterations associated with obesity. It provides valuable insights into the pathophysiological mechanisms underlying obesity, thereby opening avenues for the discovery of potential biomarkers and the development of personalized medicine in obesity.
PubMed: 38703299
DOI: 10.1007/s13679-024-00561-4 -
Pulmonary Pharmacology & Therapeutics Aug 2023COPD pathogenesis is frequently associated with endoplasmic reticulum stress (ER stress) progression. Targeting the major unfolded protein response (UPR) branches in the... (Review)
Review
COPD pathogenesis is frequently associated with endoplasmic reticulum stress (ER stress) progression. Targeting the major unfolded protein response (UPR) branches in the ER stress pathway may provide pharmacotherapeutic selection strategies for treating COPD and enable relief from its symptoms. In this study, we aimed to systematically review the potential role of the ER stress inhibitors of major UPR branches (IRE1, PERK, and ATF6) in COPD-related studies and determine the current stage of knowledge in this field. The systematic review was carried out adhering to the PRISMA checklist based on published studies obtained from specific keyword searches of three databases, namely PubMed, ScienceDirect and Springer Database. The search was limited to the year 2000-2022 which includes all in vitro studies, in vivo studies and clinical trials related to the application of ER stress inhibitors toward COPD-induced models and disease. The risk of bias was evaluated using the QUIN, SYRCLE, revised Cochrane risk of bias tool for randomized trials (RoB 2.0) and NIH tool respectively. A total of 7828 articles were screened from three databases and a final total of 37 studies were included in the review. The ER stress and UPR pathways are potentially useful to prevent COPD progression and attenuate the exacerbation of COPD and related symptoms. Interestingly, the off-target effects from inhibition of the UPR pathway may be desirable or undesirable depending on context and therapeutic applications. Targeting the UPR pathway could have complex consequences as the production of ER molecules involved in folding may be impaired which could continuously provoke misfolding of proteins. Although several emerging compounds were noted to be potentially useful for targeted therapy against COPD, clinical studies have yet to be thoroughly explored.
Topics: Humans; eIF-2 Kinase; Endoplasmic Reticulum Stress; Unfolded Protein Response; Pulmonary Disease, Chronic Obstructive
PubMed: 37201652
DOI: 10.1016/j.pupt.2023.102218 -
Annual Review of Biochemistry Jun 2021Codon usage bias, the preference for certain synonymous codons, is found in all genomes. Although synonymous mutations were previously thought to be silent, a large body...
Codon usage bias, the preference for certain synonymous codons, is found in all genomes. Although synonymous mutations were previously thought to be silent, a large body of evidence has demonstrated that codon usage can play major roles in determining gene expression levels and protein structures. Codon usage influences translation elongation speed and regulates translation efficiency and accuracy. Adaptation of codon usage to tRNA expression determines the proteome landscape. In addition, codon usage biases result in nonuniform ribosome decoding rates on mRNAs, which in turn influence the cotranslational protein folding process that is critical for protein function in diverse biological processes. Conserved genome-wide correlations have also been found between codon usage and protein structures. Furthermore, codon usage is a major determinant of mRNA levels through translation-dependent effects on mRNA decay and translation-independent effects on transcriptional and posttranscriptional processes. Here, we discuss the multifaceted roles and mechanisms of codon usage in different gene regulatory processes.
Topics: Animals; Codon Usage; Eukaryota; Gene Expression; Humans; Protein Biosynthesis; Protein Folding; RNA, Messenger; RNA, Transfer; Ribosomes
PubMed: 33441035
DOI: 10.1146/annurev-biochem-071320-112701 -
Frontiers in Immunology 2022Mammalian neuraminidases (NEUs), also known as sialidases, are enzymes that cleave off the terminal neuraminic, or sialic, acid resides from the carbohydrate moieties of...
Mammalian neuraminidases (NEUs), also known as sialidases, are enzymes that cleave off the terminal neuraminic, or sialic, acid resides from the carbohydrate moieties of glycolipids and glycoproteins. A rapidly growing body of literature indicates that in addition to their metabolic functions, NEUs also regulate the activity of their glycoprotein targets. The simple post-translational modification of NEU protein targets-removal of the highly electronegative sialic acid-affects protein folding, alters protein interactions with their ligands, and exposes or covers proteolytic sites. Through such effects, NEUs regulate the downstream processes in which their glycoprotein targets participate. A major target of desialylation by NEUs are mucins (MUCs), and such post-translational modification contributes to regulation of disease processes. In this review, we focus on the regulatory roles of NEU-modified MUCs as coordinators of disease pathogenesis in fibrotic, inflammatory, infectious, and autoimmune diseases. Special attention is placed on the most abundant and best studied NEU1, and its recently discovered important target, mucin-1 (MUC1). The role of the NEU1 - MUC1 axis in disease pathogenesis is discussed, along with regulatory contributions from other MUCs and other pathophysiologically important NEU targets.
Topics: Animals; Glycoproteins; Immune System Diseases; Mammals; Mucins; N-Acetylneuraminic Acid; Neuraminidase
PubMed: 35479093
DOI: 10.3389/fimmu.2022.883079 -
Glycobiology May 2024Multivalency in lectins plays a pivotal role in influencing glycan cross-linking, thereby affecting lectin functionality. This multivalency can be achieved through...
Multivalency in lectins plays a pivotal role in influencing glycan cross-linking, thereby affecting lectin functionality. This multivalency can be achieved through oligomerization, the presence of tandemly repeated carbohydrate recognition domains, or a combination of both. Unlike lectins that rely on multiple factors for the oligomerization of identical monomers, tandem-repeat lectins inherently possess multivalency, independent of this complex process. The repeat domains, although not identical, display slightly distinct specificities within a predetermined geometry, enhancing specificity, affinity, avidity and even oligomerization. Despite the recognition of this structural characteristic in recently discovered lectins by numerous studies, a unified criterion to define tandem-repeat lectins is still necessary. We suggest defining them multivalent lectins with intrachain tandem repeats corresponding to carbohydrate recognition domains, independent of oligomerization. This systematic review examines the folding and phyletic diversity of tandem-repeat lectins and refers to relevant literature. Our study categorizes all lectins with tandemly repeated carbohydrate recognition domains into nine distinct folding classes associated with specific biological functions. Our findings provide a comprehensive description and analysis of tandem-repeat lectins in terms of their functions and structural features. Our exploration of phyletic and functional diversity has revealed previously undocumented tandem-repeat lectins. We propose research directions aimed at enhancing our understanding of the origins of tandem-repeat lectin and fostering the development of medical and biotechnological applications, notably in the design of artificial sugars and neolectins.
Topics: Animals; Humans; Lectins; Tandem Repeat Sequences
PubMed: 38857376
DOI: 10.1093/glycob/cwae041