Protein-protein interactions

Introduction: The objective of this study is to investigate the interaction between Candida albicans and human proteins during oral candidiasis, with the aim of identifying pathways through which the pathogen subverts host cells.Methods: A comprehensive list of interactions between human proteins and C. albicans was obtained from the Human Protein Interaction Database using specific screening criteria. Then, the genes that exhibit differential expression during oral candidiasis in C. albicans were mapped with the list of human–Candida interactions to identify the corresponding host proteins. The identified host proteins were further compared with proteins specific to the tongue, resulting in a final list of 99 host proteins implicated in oral candidiasis. The interactions between host proteins and C. albicans proteins were analyzed using the STRING database, enabling the construction of protein–protein interaction networks. Similarly, the gene regulatory network of Candida proteins ...

Viral infections are the cause of serious infirmities in humans and kill millions of people every year. Management of viral diseases is one of the challenges faced by the whole world which needs improvement in prevention and treatment options. Complete understanding of the consequences of viral proteins interaction network on host physiology is essential. Towards this goal, deciphering viral protein-protein interactions is one of the perspective which can help in our understanding about the basis of viral pathogenesis and the development of new antivirals. Indeed, viral infection network based on viral-viral proteins will provide an elusive and investigative framework to articulate rationalize drug discovery based on proteomics scale of viruses. In this study, proteomics a collection of viral-viral protein interactions reporting different studies of Hepatitis C virus, Influenza A virus, Dengue virus and SARS Coronavirus. Our effort of protein-interactions was focused on different st...

Metabolism is the consortium of reactions within a cell which directs a variety of processes including energy synthesis, signalling and the behaviour of a biological system. Metabolic networks, and more specifically the activity of enzymes within them, provide an accurate status of how cellular information is being executed. The performance of these networks and their ability to siphon metabolites in a number of directions may be the difference between a healthy and diseased state. Blue native polyacrylamide gel electrophoresis (BN-PAGE), owing to its simplicity and wide-ranging applications, permits the inspection of these nodules. The separation of proteins and enzyme complexes in their native format enables the exploration of enzymatic activity in metabolic networks via in-gel assays. These are quick, specific, and amenable to further studies. This electrophoretic technology not only enables the visualization of enzymatic efficacy but reveals the crosstalk among enzymes and their interactions with other organellar partners.

Members of the TOPLESS gene family emerged recently as key players in gene repression in several mechanisms, especially in auxin perception. The TOPLESS genes constitute, in 'higher-plant' genomes, a small multigenic family comprising four to 11 members. In this study, this family was investigated in tomato, a model plant for Solanaceae species and fleshy fruits. Six open reading frames predicted to encode topless-like proteins (SlTPLs) containing the canonical domains (LisH, CTLH, and two WD40 repeats) were identified in the tomato genome. Nuclear localization was confirmed for all members of the SlTPL family with the exception SlTPL6, which localized at the cytoplasm and was excluded from the nucleus. SlTPL genes displayed distinctive expression patterns in different tomato organs, with SlTPL1 showing the highest levels of transcript accumulation in all tissues tested except in ripening fruit where SlTPL3 and SlTPL4 were the most prominently expressed. To gain insight into the specificity of the different TOPLESS paralogues, a protein-protein interaction map between TOPLESS and auxin/indole-3-acetic acid (Aux/IAA) proteins was built using a yeast two-hybrid approach. The PPI map enabled the distinction of two patterns: TOPLESS isoforms interacting with the majority of Aux/IAA, and isoforms with limited capacity for interaction with these protein partners. Interestingly, evolutionary analyses of the TOPLESS gene family revealed that the highly expressed isoforms (SlTPL1, SlTPL3, and SlTPL4) corresponded to the three TPL-related genes undergoing the strongest purifying selection, while the selection was much weaker for SlTPL6, which was expressed at a low level and encoded a protein lacking the capacity to interact with Aux/IAAs.

Mammalian excitatory synapses express diverse types of synaptic plasticity. A major challenge in neuroscience is to understand how a neuron utilizes different types of plasticity to sculpt brain development, function, and behavior. Neuronal activity-induced expression of the immediate early protein, Arc, is critical for long-term potentiation and depression of synaptic transmission, homeostatic synaptic scaling, and adaptive functions such as long-term memory formation. However, the molecular basis of Arc protein function as a regulator of synaptic plasticity and cognition remains a puzzle. Recent work on the biophysical and structural properties of Arc, its protein-protein interactions and post-translational modifications have shed light on the issue. Here, we present Arc protein as a flexible, multifunctional and interactive hub. Arc interacts with specific effector proteins in neuronal compartments (dendritic spines, nuclear domains) to bidirectionally regulate synaptic strength by distinct molecular mechanisms. Arc stability, subcellular localization, and interactions are dictated by synaptic activity and post-translational modification of Arc. This functional versatility and context-dependent signaling supports a view of Arc as a highly specialized master organizer of long-term synaptic plasticity, critical for information storage and cognition.

Mcl-1, an anti-apoptotic member of the Bcl-2 protein family, is overexpressed in a broad range of human cancers and plays a critical role in conferring resistance to chemotherapy. In the course of screening a natural product-like library of sesquiterpenoid analogs, we identified substituted hexahydronaphthalenes that showed activity against the Mcl-1/BimBH3 interaction in vitro. Here, we describe the synthesis of a small library of analogs and their biological evaluation. The most potent inhibitor in the series (19) exhibits an IC 50 of 8.3 μM by ELISA and disrupts the interaction between endogenously expressed Mcl-1 and Bim in cultured MDA-MB-468 breast cancer cells.

An increasing number of reports suggest an association between COVID-19 infection and initiation or acceleration of neurodegenerative diseases including Alzheimer's disease (AD) and Creutzfeldt-Jakob disease (CJD). Both these diseases and several other neurodegenerative diseases are caused by conversion of human proteins into a misfolded, aggregated amyloid fibril state. The fibril formation process is self-perpetuating by seeded conversion from preformed fibril seeds. We recently described a plausible mechanism for amyloid fibril formation of SARS-CoV-2 spike protein. Spike-protein formed amyloid fibrils upon cleavage by neutrophil elastase, abundant in the inflammatory response to COVID-19 infection. We here provide evidence of significant Spike-amyloid fibril seeded acceleration of amyloid formation of CJD associated human prion protein (HuPrP) using an in vitro conversion assay. By seeding the HuPrP conversion assay with other in vitro generated disease associated amyloid fi...

Coronaviruses (CoVs) have been the cause of human respiratory syndromes for many years. In recent years, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), as the cause of the coronavirus disease (COVID-19) global pandemic has imposed enormous health care issues and economic burden. The recent emerging SARS-CoV-2 variants with higher transmissibility and substantial immune evasion, have highlighted the importance of sustainable and imperative solutions to develop novel therapeutics other than vaccination to combat CoVs infections. In the search for promising antivirals for coronaviruses, besides receptor recognition and virus entry, efforts have concentrated on targeting other molecular machineries of the virus, such as the replication/transcription complex (RTC). Here, the key interacting residues that mediate the protein-protein interactions (PPIs) of nsp10 with nsp16 and nsp14 have been comprehensively analyzed. Consequently, the key residues' interaction maps,...

Molecular mechanisms underlying the pathogenesis and progression of malignant thyroid cancers, such as follicular thyroid carcinomas (FTCs), and how these differ from benign thyroid lesions, are poorly understood. In this study, we employed network-based integrative analyses of FTC and benign follicular thyroid adenoma (FTA) lesion transcriptomes to identify key genes and pathways that differ between them. We first analysed a microarray gene expression dataset (Gene Expression Omnibus GSE82208, n = 52) obtained from FTC and FTA tissues to identify differentially expressed genes (DEGs). Pathway analyses of these DEGs were then performed using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) resources to identify potentially important pathways, and protein-protein interactions (PPIs) were examined to identify pathway hub genes. Our data analysis identified 598 DEGs, 133 genes with higher and 465 genes with lower expression in FTCs. We identified four significant p...

Judo athletes are highly susceptible to chronic muscle damage and oxidative injury. The purpose of this study was to investigate the effect of 8 weeks judo training program on oxidative stress biomarkers and creatine kinase (CK) in male judo athletes. Twenty-four elite male judo athletes were randomly divided into control (C; n=12) and experimental groups (E; n =12). The experimental group (E) performed judo training 6 days/week for 8 weeks. The control group (C) did not participate in any exercise training program during the study. Blood samples were collected 24 h before the beginning of the training protocol, 24 h post-exercise in week 8 and after one week of recovery, to determine hemoglobin (Hb), hematocrit (HCT), blood viscosity, plasma malondialdehyde (MDA), serum protein carbonyls (PC), plasma fibrinogen and serum CK. Eight weeks of judo training increased maximal oxygen consumption (VO2 max), decreased body mass and fat% in E group. In E group, the levels of MDA, fibrinogen...

The objective of the current study was to enhance the proteolytic stability of peptide-based inhibitors that target critical protein-protein interactions at the dimerization interface of Leishmania infantum trypanothione reductase (Li-TryR) using a backbone modification strategy. To achieve this goal we carried out the synthesis, proteolytic stability studies and biological evaluation of a small library of α/β 3-peptide foldamers of different length (from 9-mers to 13-mers) and different α→β substitution patterns related to prototype linear α-peptides. We show that several 13-residue α/β 3-peptide foldamers retain inhibitory potency against the enzyme (in both activity and dimerization assays) while they are far less susceptible to proteolytic degradation than an analogous α-peptide. The strong dependence of the binding affinities for Li-TryR on the length of the α,β-peptides is supported by theoretical calculations on conformational ensembles of the resulting complexes. The conjugation of the most proteolytically stable α/β-peptide with oligoarginines results in a molecule with potent activity against L. infantum promastigotes and amastigotes.

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Many protein families involved in protein-protein interaction (PPI) contain sub-families that interact with different protein binding partners. We have applied the Sequence Harmony method (SH), which is able to detect specificity sites from a multiple sequence alignment (MSA) containing sub-families. The input was a dataset of MSAs of interacting protein families, each time containing a set of non-interacting paralogous sequences. Exploiting the differences in sequence conservation between the binding and non-binding groups by SH, we demonstrate that predicted specificity residues turn out to reside on the protein surface. We also show that we can select interface residues with approximately 14% coverage (true-positive rate) at 27% error (false-positive rate).

Yeast two-hybrid (Y2H) screens often produce vastly non-overlapping interaction data when the screens are conducted in different laboratories, or use different vectors, strains, or reporter genes. Here we investigate the underlying reasons for such inconsistencies and compare the effect of 7 different vectors and their Y2H interactions. Genome-wide array screens with 49 motility-related baits from Treponema pallidum yielded 77 and 165 interactions with bait vectors pLP-GBKT7 and pAS1-LP, respectively, including 21 overlapping interactions. In addition, 90 motility-related proteins from E. coli were tested in all pairwise combinations and yielded 140 interactions when tested with pGBKT7g/pGADT7g vectors but only 47 when tested with pDEST32/pDEST22. We discuss the factors that determine these effects, including copy number, the nature of the fusion protein, and species-specific differences that explain non-conserved interactions among species. The pDEST22/pDEST32 vectors produce a higher fraction of interactions that are conserved and that are biologically relevant when compared to the pGBKT7/pGADT7-related vectors, but the latter appear to be more sensitive and thus detect more interactions. Keywords protein-protein interactions; yeast two-hybrid vectors; bacterial motility; flagella Recently Braun et al. [5] compared Y2H systems to completely different methodologies such as LUMIER [6] and NAPPA [7] and found dramatic differences. In addition, they also used two slightly different Y2H systems and showed that there are differences between CEN vectors

Dietary fibres are regarded as the source of polysaccharides and antioxidants such as polyphenols. However, addition of dietary fibre to bread causes significant reduction in its quality. The bread quality is connected with the structure of gluten proteins. For this reason, Fourier transform Raman spectroscopy was applied to determine changes in structure of gluten proteins modified by seven dietary fibres. The fibres were added to model flour reconstituted with wheat gluten and wheat starch. The model flour was used to provide gluten proteins of definite structure. The obtained results showed that six out of seven fibres caused similar changes in β‐turn structures. The appearance of the band at 1642 cm−1 and the shift toward lower wavenumbers of the band at 1670 cm−1 in the difference spectra indicated hydrogen bonding of carbonyl groups in β‐turns leading to protein folding/aggregation. Addition of fibre preparations caused also changes in conformation of disulfide bridges (S–S), ...

Background: Large scale understanding of complex and dynamic alterations in cellular and subcellular levels during cancer in contrast to normal condition has facilitated the emergence of sophisticated systemic approaches like network biology in recent times. As most biological networks show modular properties, the analysis of differential modularity between normal and cancer protein interaction networks can be a good way to understand cancer more significantly. Two aspects of biological network modularity e.g. detection of molecular complexes (potential modules or clusters) and identification of crucial nodes forming the overlapping modules have been considered in this regard. Methods: In the current study, the computational analysis of previously published protein interaction networks (PINs) has been conducted to identify the molecular complexes and crucial nodes of the networks. Protein molecules involved in ten major cancer signal transduction pathways were used to construct the networks based on expression data of five tissues e.g. bone, breast, colon, kidney and liver in both normal and cancer conditions. MCODE (molecular complex detection) and ModuLand methods have been used to identify the molecular complexes and crucial nodes of the networks respectively. Results: In case of all tissues, cancer PINs show higher level of clustering (formation of molecular complexes) than the normal ones. In contrast, lower level modular overlapping is found in cancer PINs than the normal ones. Thus a proposition can be made regarding the formation of some giant nodes in the cancer networks with very high degree and resulting in reduced overlapping among the network modules though the predicted molecular complex numbers are higher in cancer conditions. Conclusion: The study predicts some major molecular complexes that might act as the important regulators in cancer progression. The crucial nodes identified in this study can be potential drug targets to combat cancer.

Because streptavidin is a homotetramer, it can bind multiple biotinylated ligands and cause target aggregation. To allow biotin detection without clustering, we previously engineered monomeric streptavidin (mSA) that is structurally similar to a single streptavidin subunit. Introducing the S25H mutation near the binding site increases the biotin dissociation half-life t 1/2 to 83 minutes. The slowly dissociating mutant, mSA2, is useful in imaging studies because it allows stable labeling of biotinylated targets. We show that mSA2 conjugated with Alexa 488 binds biotinylated receptors on HEK293 with high specifi city, and bound mSA2-Alexa488 does not dissociate signifi cantly during an imaging study lasting 50 minutes. As a structural monomer, mSA2 can be fused to other proteins to create bifunctional molecules. We tested the use of mSA2 in proximity dependent biotinylation, in which mSA2 is fused to a peptide or a protein that binds a protein of interest (POI) and is used to recruit photoactivatable biotin (PA-biotin) to the target molecule. Once the resulting cluster of interacting proteins is subjected to UV-initiated distance-dependent biotinylation, subsequent affi nity purifi cation of biotinylated proteins on streptavidin beads can identify protein molecules that interact with POI. In addition to proteins that directly interact with the mSA2 fusion, mSA2 also induces biotinylation of other proteins that are associated through a series of noncovalent interactions. We show that mSA2 fused to an antibody recognition domain can be recruited to the kinase Erk-2 using a commercially available antibody and induce biotinylation of a known Erk-2 substrate, GST-Elk-1. Therefore, mSA2 can be used to implement proximity dependent biotinylation and detect transient enzyme-substrate interactions.

Because streptavidin is a homotetramer, it can bind multiple biotinylated ligands and cause target aggregation. To allow biotin detection without clustering, we previously engineered monomeric streptavidin (mSA) that is structurally similar to a single streptavidin subunit. Introducing the S25H mutation near the binding site increases the biotin dissociation half-life t1/2 to 83 minutes. The slowly dissociating mutant, mSA2, is useful in imaging studies because it allows stable labeling of biotinylated targets. We show that mSA2 conjugated with Alexa 488 binds biotinylated receptors on HEK293 with high specificity, and bound mSA2–Alexa488 does not dissociate significantly during an imaging study lasting 50 minutes. As a structural monomer, mSA2 can be fused to other proteins to create bifunctional molecules. We tested the use of mSA2 in proximity dependent biotinylation, in which mSA2 is fused to a peptide or a protein that binds a protein of interest (POI) and is used to recruit ph...

In recent years, the emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), as the cause of the coronavirus disease (COVID-19) global pandemic, and its variants, especially those with higher transmissibility and substantial immune evasion, have highlighted the imperative for developing novel therapeutics as sustainable solutions other than vaccination to combat coronaviruses (CoVs). Beside receptor recognition and virus entry, members of the SARS-CoV-2 replication/transcription complex are promising targets for designing antivirals. Here, the interacting residues that mediate protein-protein interactions (PPIs) of nsp10 with nsp16 and nsp14 were comprehensively analyzed, and the key residues' interaction maps, interaction energies, structural networks, and dynamics were investigated. Nsp10 stimulates both nsp14's exoribonuclease (ExoN) and nsp16's 2′O-methyltransferase (2′O-MTase). Nsp14 ExoN is an RNA proofreading enzyme that supports replication fidelity. Nsp16 2′O-MTase is responsible for the completion of RNA capping to ensure efficient replication and translation and escape from the host cell's innate immune system. The results of the PPIs analysis proposed crucial information with implications for designing SARS-CoV-2 antiviral drugs. Based on the predicted shared protein-protein interfaces of the nsp16-nsp10 and nsp14-nsp10 interactions, a set of dual-target peptide inhibitors was designed. The designed peptides were evaluated by molecular docking, peptide-protein interaction analysis, and free energy calculations, and then further optimized by in silico saturation mutagenesis. Based on the predicted evolutionary conservation of the interacted target residues among CoVs, the designed peptides have the potential to be developed as dual target pan-coronavirus inhibitors.

This review discusses the discovery, epidemiology, and gene etiology of Alzheimer's disease (AD). It also highlights the Alzheimer's gender disparity common comorbid and modifiable risk factors. AD is a progressive neurodegenerative condition that impacts both daily activities and social interactions. With the rise in life expectancy and demographic aging, the global prevalence of AD is expected to increase further, particularly in developing peoples, resulting in a significant burden of disease. Its prevalence in the general population increases dramatically with age; it affects approximately 80% of patients aged ≥ 75 years. AD that occurs before the age of 65, known as early-onset AD (EOAD), is not as extensively studied as late-onset AD (LOAD), even though EOAD often presents with a more aggressive disease progression. AD is a complex and multifactorial disorder influenced by genetic susceptibility and environmental factors over the individual's life. Sex-specific risk factors of dementia for women, including pregnancy, menopause, and preeclampsia, account for the rise of AD among women compared to men. Identifying modifier genes has facilitated the control of APOE genes and their co-expressed genes. Nevertheless, exploring new gene modifiers may enhance a better understanding of intricate AD characteristics and hold potential therapeutic benefits for individuals with AD.

The P22 tailspike protein is an intensely studied protein whose structure and sequence has been described. However, a study, describing important protein interactions related to its function at the N-terminal domain, has been lacking. The P22 tailspike protein (TSP) consists of three identical polypeptide chains of 666aa. The first 108 of the 666aa in the P22 TSP form a trimeric N-terminal domain (NTD). Each of the three chains of the trimeric NTD contributes to the formation of a dome-like structure. Our studies suggest that a short stretch of amino acids located within the first fifteen amino acids of the P22 TSP NTD is critical for the stability of the dome structure formed by the first 108aa of the P22 TSP NTD. The first 23aa are located within this dome-like structure and have been dubbed the "stem" of the NTD. Although amino acid residues in the first 15aa (lower stem) are critical, deletion analysis and in vitro assembly studies implicate the rest of the stem in additional stabilizing interactions. Our studies implicate a common protein-protein interaction motif made up of interchain hydrophobic contacts between adjacent chains

The identification of disease-related protein-protein interactions (PPIs) creates objective conditions for their pharmacological modulation. The contact area (interfaces) of the vast majority of PPIs has some features, such as geometrical and biochemical complementarities, "hot spots", as well as an extremely low mutation rate that give us key knowledge to influence these PPIs. Exogenous regulation of PPIs is aimed at both inhibiting the assembly and/or destabilization of protein complexes. Often, the design of such modulators is associated with some specific problems in targeted delivery, cell penetration and proteolytic stability, as well as selective binding to cellular targets. Recent progress in interfacial peptide design has been achieved in solving all these difficulties and has provided a good efficiency in preclinical models (in vitro and in vivo). The most promising peptide-containing therapeutic formulations are under investigation in clinical trials. In this review, we update the current state-of-the-art in the field of interfacial peptides as potent modulators of a number of disease-related PPIs. Over the past years, the scientific interest has been focused on following clinically significant heterodimeric PPIs MDM2/p53, PD-1/PD-L1, HIF/HIF, NRF2/KEAP1, RbAp48/MTA1, HSP90/CDC37, BIRC5/CRM1, BIRC5/XIAP, YAP/TAZ-TEAD, TWEAK/FN14, Bcl-2/Bax, YY1/AKT, CD40/CD40L and MINT2/APP.

The VHL tumour suppressor gene codes for von-Hippel Lindau (VHL) protein which acts by association with Elongin C and Hypoxia Inducing Factor-1 alpha (HIF). Two functional sub-domains in the protein model of VHL contain binding sites for these proteins. Alpha domain of VHL protein contains the binding site for Elongin C (tumorigenic cluster A) whereas; the beta domain contains the binding site for HIF-1 alpha (tumorigenic cluster B). The complex formation between VHL, Elongin C and HIF- 1 alpha protein is crucial for the regulation of ubiquitin dependent proteolysis of oncogenic proteins. Henceforth defects in the complex formation may lead to von-Hippel Lindau disease. A majority of VHL disease causing mutations found to occur in these binding sites are highly conserved. In this computational analysis, we have predicted the functional effect of Single amino acid Polymorphisms (SAPs) in VHL-interacting proteins with the aid of pathogenicity and protein stability predictors. Furtherm...

Viral infections are the cause of serious infirmities in humans and kill millions of people every year. Management of viral diseases is one of the challenges faced by the whole world which needs improvement in prevention and treatment options. Complete understanding of the consequences of viral proteins interaction network on host physiology is essential. Towards this goal, deciphering viral protein-protein interactions is one of the perspective which can help in our understanding about the basis of viral pathogenesis and the development of new antivirals. Indeed, viral infection network based on viral-viral proteins will provide an elusive and investigative framework to articulate rationalize drug discovery based on proteomics scale of viruses. In this study, proteomics a collection of viral-viral protein interactions reporting different studies of Hepatitis C virus, Influenza A virus, Dengue virus and SARS Coronavirus. Our effort of protein-interactions was focused on different st...

O-GlcNAcylation is a post-translational modification that influences tyrosine phosphorylation in healthy and malignant cells. O-GlcNAc is a product of the hexosamine biosynthetic pathway, a side pathway of glucose metabolism. It is essential for cell survival and proper gene regulation, mirroring the metabolic status of a cell. STAT3 and STAT5 proteins are essential transcription factors that can act in a mutational context-dependent manner as oncogenes or tumor suppressors. They regulate gene expression for vital processes such as cell differentiation, survival, or growth, and are also critically involved in metabolic control. The role of STAT3/5 proteins in metabolic processes is partly independent of their transcriptional regulatory role, but is still poorly understood. Interestingly, STAT3 and STAT5 are modified by O-GlcNAc in response to the metabolic status of the cell. Here, we discuss and summarize evidence of O-GlcNAcylation-regulating STAT function, focusing in particular ...

Vibrio parahaemolyticus is an important cause of gastroenteritis resulting from the consumption of raw or undercooked shellfish. The V. parahaemolyticus genome revealed the presence of two type III secretion systems (T3SS); one on each of the two chromosomes. To date, four effectors have been identified as secreted by the chromosome 1 T3SS (T3SS1). For some effectors, efficient secretion requires a cytosolic chaperone that is often encoded in close proximity to its cognate effector. In this study, we identified VPA0451 as the specific chaperone for the T3SS1 effector, VPA0450. VPA0451 is structurally similar to known T3SS chaperones. It is required for efficient VPA0450 secretion while not affecting the secretion of other T3SS1 effectors, suggesting it is a class 1A single cargo chaperone. VPA0450 translocation into the host cell membrane requires VPA0451. VPA0451 binds directly to VPA0450, and amino acids 25-100 contribute to this activity. Taken together, we conclude that VPA0451 is the cognate chaperone for the effector VPA0450 and is the second T3SS1 chaperone identified to date.

We analyze the characteristics of protein-protein interfaces using the largest datasets available from the Protein Data Bank (PDB). We start with a comparison of interfaces with protein cores and noninterface surfaces. The results show that interfaces differ from protein cores and non-interface surfaces in residue composition, sequence entropy, and secondary structure. Since interfaces, protein cores, and non-interface surfaces have different solvent accessibilities, it is important to investigate whether the observed differences are due to the differences in solvent accessibility or differences in functionality. We separate out the effect of solvent accessibility by comparing interfaces with a set of residues having the same solvent accessibility as the interfaces. This strategy reveals residue distribution propensities that are not observable by comparing interfaces with protein cores and noninterface surfaces. Our conclusions are that there are larger numbers of hydrophobic residues, particularly aromatic residues, in interfaces, and the interactions apparently favored in interfaces include the opposite charge pairs and hydrophobic pairs. Surprisingly, Pro-Trp pairs are over represented in interfaces, presumably because of favorable geometries. The analysis is repeated using three datasets having different constraints on sequence similarity and structure quality. Consistent results are obtained across these datasets. We have also investigated separately the characteristics of heteromeric interfaces and homomeric interfaces.

Structural and functional coupling of Hsp90-and Sgt1-centred multi-protein complexes This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits distribution, and reproduction in any medium, provided the original author and source are credited. This license does not permit commercial exploitation or the creation of derivative works without specific permission.

The tumour necrosis factor-like weak inducer of apoptosis (TWEAK) is a member of the tumour necrosis factor ligand family and has been shown to be overexpressed in tumoral cells together with the fibroblast growth factor–inducible 14 (Fn14) receptor. TWEAK-Fn14 interaction triggers a set of intracellular pathways responsible for tumour cell invasion and migration, as well as proliferation and angiogenesis. Hence, modulation of the TWEAK-Fn14 interaction is an important therapeutic goal. The targeting of protein-protein interactions by external agents, e.g., drugs, remains a substantial challenge. Given their intrinsic features, as well as recent advances that improve their pharmacological profiles, peptides have arisen as promising agents in this regard. Here, we report, by in silico structural design validated by cell-based and in vitro assays, the discovery of four peptides able to target TWEAK. Our results show that, when added to TWEAK-dependent cellular cultures, peptides cause...

Systemic lupus erythematosus (SLE) is an autoimmune inflammatory disorder that is clinically complex and has increased production of autoantibodies. Via emerging technologies, researchers have identified genetic variants, expression profiling of genes, animal models, and epigenetic findings that have paved the way for a better understanding of the molecular and genetic mechanisms of SLE. Our current study aimed to illustrate the essential genes and molecular pathways that are potentially involved in the pathogenesis of SLE. This study incorporates the gene expression profiling data of the microarray dataset GSE30153 from the Gene Expression Omnibus (GEO) database, and differentially expressed genes (DEGs) between the B-cell transcriptomes of SLE patients and healthy controls were screened using the GEO2R web tool. The identified DEGs were subjected to STRING analysis and Cytoscape to explore the protein-protein interaction (PPI) networks between them. The MCODE (Molecular Complex Detection) plugin of Cytoscape was used to screen the cluster subnetworks that are highly interlinked between the DEGs. Subsequently, the clustered DEGs were subjected to functional annotation with ClueGO/CluePedia to identify the significant pathways that were enriched. For integrative analysis, we used GeneGo Metacore TM , a Cortellis Solution software, to exhibit the Gene Ontology (GO) and enriched pathways between the datasets. Our study identified 4 upregulated and 13 downregulated genes. Analysis of GO and functional enrichment using ClueGO revealed the pathways that were statistically significant, including pathways involving T-cell costimulation, lymphocyte costimulation, negative regulation of vascular permeability, and B-cell receptor signaling. The DEGs were mainly enriched in metabolic networks such as the phosphatidylinositol-3,4,5-triphosphate pathway and the carnitine pathway. Additionally, potentially enriched pathways, such as the signaling pathways induced by oxidative stress and reactive oxygen species (ROS), chemotaxis and lysophosphatidic acid signaling induced via G protein-coupled receptors (GPCRs), and the androgen

Systemic lupus erythematosus (SLE) is an autoimmune inflammatory disorder that is clinically complex and has increased production of autoantibodies. Via emerging technologies, researchers have identified genetic variants, expression profiling of genes, animal models, and epigenetic findings that have paved the way for a better understanding of the molecular and genetic mechanisms of SLE. Our current study aimed to illustrate the essential genes and molecular pathways that are potentially involved in the pathogenesis of SLE. This study incorporates the gene expression profiling data of the microarray dataset GSE30153 from the Gene Expression Omnibus (GEO) database, and differentially expressed genes (DEGs) between the B-cell transcriptomes of SLE patients and healthy controls were screened using the GEO2R web tool. The identified DEGs were subjected to STRING analysis and Cytoscape to explore the protein-protein interaction (PPI) networks between them. The MCODE (Molecular Complex Detection) plugin of Cytoscape was used to screen the cluster subnetworks that are highly interlinked between the DEGs. Subsequently, the clustered DEGs were subjected to functional annotation with ClueGO/CluePedia to identify the significant pathways that were enriched. For integrative analysis, we used GeneGo Metacore TM , a Cortellis Solution software, to exhibit the Gene Ontology (GO) and enriched pathways between the datasets. Our study identified 4 upregulated and 13 downregulated genes. Analysis of GO and functional enrichment using ClueGO revealed the pathways that were statistically significant, including pathways involving T-cell costimulation, lymphocyte costimulation, negative regulation of vascular permeability, and B-cell receptor signaling. The DEGs were mainly enriched in metabolic networks such as the phosphatidylinositol-3,4,5-triphosphate pathway and the carnitine pathway. Additionally, potentially enriched pathways, such as the signaling pathways induced by oxidative stress and reactive oxygen species (ROS), chemotaxis and lysophosphatidic acid signaling induced via G protein-coupled receptors (GPCRs), and the androgen

The interleukin (IL)-1 family is a major proinflammatory cytokine family, ranging from the well-studied IL-1s to the most recently discovered IL-33. As a new focus, IL-33 has attracted extensive research for its crucial immunoregulatory roles, leading to the development of notable monoclonal antibodies as clinical candidates. Efforts to develop small molecules disrupting IL-33/ST2 interaction remain highly desired but encounter challenges due to the shallow and featureless interfaces. The information from relative cytokines has shown that traditional binding site identification methods still struggle in mapping cryptic sites, necessitating dynamic approaches to uncover druggable pockets on IL-33. Here, we employed mixed-solvent molecular dynamics (MixMD) simulations with diverse-property probes to map the hotspots of IL-33 and identify potential binding sites. The protocol was first validated using the known binding sites of two IL-1 family members and then applied to the structure of IL-33. Our simulations revealed several binding sites and proposed sidechain rearrangements essential for the binding of a known inhibitor, aligning well with experimental NMR findings. Further microsecond-time scale simulations of this IL-33-protein complex unveiled distinct binding modes with varying occurrences. These results could facilitate future efforts in developing ligands to target challenging flexible pockets of IL-33 and IL-1 family cytokines in general.

Protein-protein redocking results using shape complementarity ..1. 'Rank' is the best rank among all predicted positions whose RMSD was less than 5Å. 'N P' is the number of peaks in the predicted set which were less than 5ÅRMSD from the known position. 'Best RMSD' is the lowest RMSD among all the peaks that were shortlisted. If there were no good predictions in the top 50,000 that we choose to keep, we enter a '-' in the column for 'Rank'. The proteins are ordered by their surface areas.. . 5.5 Protein-protein redocking results using shape complementarity..2. 'Rank' is the best rank among all predicted positions whose RMSD was less than 5Å. 'N P' is the number of peaks in the predicted set which were less than 5ÅRMSD from the known position. 'Best RMSD' is the lowest RMSD among all the peaks that were shortlisted. If there were no good predictions in the top 50,000 that we choose to keep, we enter a '-' in the column for 'Rank'.

Protein is essential for all life processes, playing crucial roles such as providing structural integrity to the body and facilitating the transport of various substances within it. Understanding protein functions is critical for advancing biological science, as it aids in the improvement, regulation, and maintenance of numerous biological systems. Various methods exist to predict the functions of proteins with unknown roles, but many are time-consuming, complex, and costly. This study introduces a novel method that offers higher accuracy in predicting protein functions. It is easier, faster, and less expensive compared to many existing techniques. This new approach employs the Markov Clustering (MCL) Algorithm to cluster protein networks, followed by the application of the majority rule [3, 36] to predict protein functions.

Far UV circular dichroism (CD) and fluorescence spectroscopy were used to investigate the interaction between bovine serum albumin (BSA) and metallothionein (MT). Both spectroscopic probes gave proofs on the interaction of the two proteins. At pH 4.0, 7.0 and 9.0, BSA showed a negative increase in ellipticity at the far-UV range in the presence of MT indicating an increase in α-helical content and a decrease in β-sheet structure. In the presence of MT at pH 4.0 and 9.0, a decrease in fluorescence intensity was observed. Tryptophan fluorescence quenching experiments were also performed using acrylamide and KI as quenchers. Under acidic conditions, a four-fold increase in Stern-Volmer constant (K SV) was observed for BSA + MT. At neutral and basic conditions, a decrease in K SV values were observed which indicates conformational changes in BSA upon binding MT. These changes are close to the region where the tryptophan residues are located in the protein.