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PubMed2006

[Aptamers in clinical diagnostics].

Aptamers are single-stranded DNA or RNA oligonucleotides selected in vitro from combinatorial libraries in a process called SELEX (Systematic Evolution of Ligands by EXponential Enrichment). Aptamers play a role of artificial nucleic acid ligands that can recognize and bind to various organic or inorganic target molecules with high specificity and affinity. They can discriminate even between closely related targets and can be easily chemically modified for radioactive, fluorescent and enzymatic labeling or biostability improvement. Aptamers can thus be considered as universal receptors that rival antibodies in diagnostics as a tool of molecular recognition. To date aptamers have been successively used instead of monoclonal antibodies in flow cytometry, immunochemical sandwich assays and in vivo imaging as well to detect wide range of small or large biomolecules.

Aptamers, Nucleotide↗
PubMed2005

Interactions of the yeast SF3b splicing factor.

The U2 snRNP promotes prespliceosome assembly through interactions that minimally involve the branchpoint binding protein, Mud2p, and the pre-mRNA. We previously showed that seven proteins copurify with the yeast (Saccharomyces cerevisiae) SF3b U2 subcomplex that associates with the pre-mRNA branchpoint region: Rse1p, Hsh155p, Hsh49p, Cus1p, and Rds3p and unidentified subunits p10 and p17. Here proteomic and genetic studies identify Rcp10p as p10 and show that it contributes to SF3b stability and is necessary for normal cellular Cus1p accumulation and for U2 snRNP recruitment in splicing. Remarkably, only the final 53 amino acids of Rcp10p are essential. p17 is shown to be composed of two accessory splicing factors, Bud31p and Ist3p, the latter of which independently associates with the RES complex implicated in the nuclear pre-mRNA retention. A directed two-hybrid screen reveals a network of prospective interactions that includes previously unreported intra-SF3b contacts and SF3b interactions with the RES subunit Bud13p, the Prp5p DExD/H-box protein, Mud2p, and the late-acting nineteen complex. These data establish the concordance of yeast and mammalian SF3b complexes, implicate accessory splicing factors in U2 snRNP function, and support SF3b contribution from early pre-mRNP recognition to late steps in splicing.

Amino Acid Sequence↗
PubMed2003

A proteomic view of cell physiology of Bacillus subtilis--bringing the genome sequence to life.

The genome sequence is the "blue-print of life", and the proteomic approach brings this genome sequence to life. Simple model systems are urgently required to "train" this transformation of the genome sequence into life: why not Bacillus subtilis, the model organism for gram-positive bacteria and of functional genomics? By combination of the highly sensitive 2D protein gel electrophoresis with the identification of the protein spots by microsequencing or mass spectrometry we established a 2D protein index of Bacillus subtilis. In order to depict the entire proteome of a B. subtilis cell, alkaline, cell-wall associated, or extracellular proteins were also included. The proteins of this database (see http://microbio2.biologie.uni-greifswald.de:8880/sub2d.htm) were allocated to proteins with house-keeping functions typical of growing cells and to proteins synthesized particularly in non-growing cells. A computer-aided evaluation of the 2D gels loaded with radioactively-labeled proteins from growing or stressed/starved cells proved to be a powerful tool for the analysis of global regulation of the expression of the entire genome. This is shown for the analysis of glycolysis/TCA cycle (house keeping proteins) and for the analysis of the heat stress stimulon. For the heat stress stimulon it is demonstrated how the proteomic approach can be used: (i) to define the structure of a stimulon, (ii) to dissect stimulons into regulons, (iii) to analyze the regulation, structure, and function of unknown regulons, (iv) to define overlapping reguIons or modulons, and finally (v) to explore complex adaptational networks. Furthermore, it will be demonstrated how the "dual channel pattern comparison" or "proteomics signature" (R. VanBogelen) can be used for a comprehensive understanding or prediction of the physiological state of growing or starving cell populations. This is shown for glucose-starved cells. In order to describe the structure and function of gene regulation groups it is generally recommended to complement the proteomics approach with DNA array technologies. Further studies will focus on the analysis of the global regulation of gene expression by the proteomic approach that cannot be addressed by the application of DNA array techniques: the phosphoproteome and its implications in signal transduction; the global control of protein stability; protein targeting and protein secretion.

Adaptation, Physiological↗
PubMed2001

In vitro display technologies: novel developments and applications.

In vitro display techniques are powerful tools to select polypeptide binders against various target molecules. Novel applications include maturation of protein affinity and stability, selection for enzymatic activity, and the display of cDNA and random polypeptide libraries. Taken together, these display techniques have great potential for biotechnological, medical and proteomic applications.

Binding Sites↗
PubMedDate not supplied

Amino Acid Sequence Autocorrelation vectors and ensembles of Bayesian-Regularized Genetic Neural Networks for prediction of conformational stability of human lysozyme mutants.

Development of novel computational approaches for modeling protein properties from their primary structure is a main goal in applied proteomics. In this work, we reported the extension of the autocorrelation vector formalism to amino acid sequences for encoding protein structural information with modeling purposes. Amino Acid Sequence Autocorrelation (AASA) vectors were calculated by measuring the autocorrelations at sequence lags ranging from 1 to 15 on the protein primary structure of 48 amino acid/residue properties selected from the AAindex database. A total of 720 AASA descriptors were tested for building predictive models of the thermal unfolding Gibbs free energy change of human lysozyme mutants. In this sense, ensembles of Bayesian-Regularized Genetic Neural Networks (BRGNNs) were used for obtaining an optimum nonlinear model for the conformational stability. The ensemble predictor described about 88% and 68% variance of the data in training and test sets, respectively. Furthermore, the optimum AASA vector subset was shown not only to successfully model unfolding thermal stability but also to distribute wild-type and mutant lysozymes on a stability Self-organized Map (SOM) when used for unsupervised training of competitive neurons.

Algorithms↗
PubMed2026

Proteomics-Driven Strategies for Proximity-Inducing Drug Discovery.

In recent years, proximity-inducing drugs have emerged as a novel therapeutic modality that induces or stabilizes protein-protein interactions, especially by recruiting effector proteins to specific target proteins, thereby achieving functions beyond traditional inhibitors. The potential of proximity-inducing drugs extends beyond targeted protein degradation (TPD), as studies have demonstrated their ability to regulate biological processes such as signal transduction, gene transcription, chromatin regulation, and protein trafficking by modulating protein interaction networks. Rational discovery of proximity-inducing drugs requires clarifying their effects on protein-protein interactions, determining drug selectivity, and developing suitable ligands for drug construction. Proteomics has become a central technology in drug discovery, enabling global identification of the direct drug targets and systematic characterization of proteome-wide downstream responses. This provides a more refined map of drug mechanisms. In parallel, advances in machine learning applied to proteomic data, together with the expansion of proteome-wide ligandability maps, are further accelerating the discovery and optimization of proximity-inducing drugs. This review summarizes recent advances of proximity-inducing drugs, with a particular emphasis on how proteomics facilitates target space expansion, drug efficacy optimization, and ligandability discovery, alongside the emerging contributions of machine learning. Collectively, these insights aim to support the rational development of next-generation proximity-inducing drugs.

Drug Discovery↗
PubMed2025

A genome-wide, CRISPR-based screen reveals new requirements for translation initiation and ubiquitination in driving adipogenic fate change.

In response to excess nutrients, white adipose tissue expands by both generating new adipocytes and upregulating lipogenesis in existing adipocytes. Here, we performed a genome-wide functional CRISPR screen to identify regulators of adipogenesis in the mouse 3T3-L1 preadipocyte model. In this pooled screening strategy, we used FACS to isolate populations based on lipid content, gating for fluorescence intensity of lipophilic fluorescent BODIPY dye. Additionally, we categorized whether the gene functions primarily during mitotic clonal expansion, lipogenesis, or both. We found that translation initiation and ubiquitin-dependent protein stability regulators drive both adipogenic fate change and lipogenesis. We further supported these findings with proteomics, demonstrating that essential changes in protein reprogramming can drive or inhibit 3T3-L1 adipogenesis independent of transcription. Furthermore, we demonstrated that specific branches of the hypusination pathway, a conserved regulator of translation initiation, are critical for translating adipogenic inducers of mitotic clonal expansion and that the neddylation/ubiquitin pathway modulates insulin sensitivity during lipogenesis.

Animals↗
PubMed2026

From glycosylation to inflammation: insights from NMR-Derived GlycA and GlycB.

Post-translational modifications (PTMs) play a crucial role in increasing proteomic diversity. N-linked glycosylation acts as a key regulatory layer that influences protein stability, trafficking, circulation, and immune responses. Unlike conventional inflammatory biomarkers that measure individual proteins, nuclear magnetic resonance (NMR) spectroscopy identifies the combined signals GlycA and GlycB from glycoproteins, offering an overall view of systemic glycoprotein changes. These signals represent the N-glycosylation patterns of several abundant acute-phase proteins (APPs), giving detailed molecular insights. This review offers a detailed assessment of GlycA and GlycB as mechanistically grounded indicators of liver glycoprotein remodeling and systemic inflammation. GlycA mainly indicates the levels and structural complexity of N-acetylglucosamine (GlcNAc) and N-acetylgalactosamine (GalNAc) residues linked to acute-phase glycoproteins and glycan branching. In contrast, GlycB reflects changes in terminal sialylation, which influences glycoprotein half-life, immune recognition via lectins, and inflammatory signaling. Collectively, these biomarkers combine measurements of hepatic APP production with variations in glycan structure, offering mechanistically anchored reporters of hepatic glycoprotein remodeling. We explore the enzymatic pathways responsible for N-glycan branching, fucosylation, and sialylation, as well as the roles of major APP scaffolds in the GlycA and GlycB resonances. We also highlight the emerging clinical significance of these signals across infectious, autoimmune, cardiovascular, metabolic, neurodegenerative, and cancer-related diseases. Rather than serving simply as markers of inflammation, GlycA and GlycB provide mechanistically interpretable readouts of cytokine-driven hepatic glycoprotein remodeling and systemic immune activation, supporting their application in disease risk stratification, longitudinal monitoring, therapeutic response assessment, and precision medicine.

GlycA↗
PubMed2025

Pitavastatin, Procollagen Pathways, and Plaque Stabilization in Patients With HIV: A Secondary Analysis of the REPRIEVE Randomized Clinical Trial.

IMPORTANCE: In a mechanistic substudy of the Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE) randomized clinical trial, pitavastatin reduced noncalcified plaque (NCP) volume, but specific protein and gene pathways contributing to changes in coronary plaque remain unknown. OBJECTIVE: To use targeted discovery proteomics and transcriptomics approaches to interrogate biological pathways beyond low-density lipoprotein cholesterol (LDL-C), relating statin outcomes to reduce NCP volume and promote plaque stabilization among people with HIV (PWH). DESIGN, SETTING, AND PARTICIPANTS: This was a post hoc analysis of the double-blind, placebo-controlled, REPRIEVE randomized clinical trial. Participants underwent coronary computed tomography angiography (CTA), plasma protein analysis, and transcriptomic analysis at baseline and 2-year follow-up. The trial enrolled PWH from April 2015 to February 2018 at 31 US research sites. PWH without known cardiovascular diseases taking antiretroviral therapy and with low to moderate 10-year cardiovascular risk were eligible. Data analyses were conducted from October 2023 to February 2024. INTERVENTION: Oral pitavastatin calcium, 4 mg per day. MAIN OUTCOMES AND MEASURES: Relative change in plasma proteomics, transcriptomics, and noncalcified plaque volume among those receiving treatment vs placebo. RESULTS: Among 558 individuals (mean [SD] age, 51 [6] years; 455 male [82%]) included in the proteomics assessment, 272 (48.7%) received pitavastatin and 286 (51.3%) received placebo. After adjusting for false discovery rates, pitavastatin increased abundance of procollagen C-endopeptidase enhancer 1 (PCOLCE), neuropilin 1 (NRP-1), major histocompatibility complex class I polypeptide-related sequence A (MIC-A) and B (MIC-B), and decreased abundance of tissue factor pathway inhibitor (TFPI), tumor necrosis factor ligand superfamily member 10 (TRAIL), angiopoietin-related protein 3 (ANGPTL3), and mannose-binding protein C (MBL2). Among these proteins, the association of pitavastatin with PCOLCE (a rate-limiting enzyme of collagen deposition) was greatest, with an effect size of 24.3% (95% CI, 18.0%-30.8%; P&#x2009;<&#x2009;.001). In a transcriptomic analysis, individual collagen genes and collagen gene sets showed increased expression. Among the 195 individuals with plaque at baseline (88 [45.1%] taking pitavastatin, 107 [54.9%] taking placebo), changes in NCP volume were most strongly associated with changes in PCOLCE (%change NCP volume/log2-fold change&#x2009;=&#x2009;-31.9%; 95% CI, -42.9% to -18.7%; P&#x2009;<&#x2009;.001), independent of changes in LDL-C level. Increases in PCOLCE related most strongly to change in the fibro-fatty (<130 Hounsfield units) component of NCP (%change fibro-fatty volume/log2-fold change&#x2009;=&#x2009;-38.5%; 95% CI, -58.1% to -9.7%; P&#x2009;=&#x2009;.01) with a directionally opposite, although nonsignificant, increase in calcified plaque (%change calcified volume/log2-fold change&#x2009;=&#x2009;34.4%; 95% CI, -7.9% to 96.2%; P&#x2009;=&#x2009;.12). CONCLUSIONS AND RELEVANCE: Results of this secondary analysis of the REPRIEVE randomized clinical trial suggest that PCOLCE may be associated with the atherosclerotic plaque stabilization effects of statins by promoting collagen deposition in the extracellular matrix transforming vulnerable plaque phenotypes to more stable coronary lesions. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02344290.

Humans↗
PubMed2005

A two-hybrid screen of the yeast proteome for Hsp90 interactors uncovers a novel Hsp90 chaperone requirement in the activity of a stress-activated mitogen-activated protein kinase, Slt2p (Mpk1p).

The Hsp90 chaperone cycle catalyzes the final activation step of several important eukaryotic proteins (Hsp90 "clients"). Although largely a functional form of Hsp90, an Hsp90-Gal4p DNA binding domain fusion (Hsp90-BD) displays no strong interactions in the yeast two-hybrid system, consistent with a general transience of most Hsp90-client associations. Strong in vivo interactions are though detected when the E33A mutation is introduced into this bait, a mutation that should arrest Hsp90-client complexes at a stage where the client is stabilized, yet prevented from attaining its active form. This E33A mutation stabilized the two-hybrid interactions of the Hsp90-BD fusion with approximately 3% of the Saccharomyces cerevisiae proteome in a screen of the 6,000 yeast proteins expressed as fusions to the Gal4p activation domain (AD). Among the detected interactors were the two stress-activated mitogen-activated protein (MAP) kinases of yeast, Hog1p and Slt2p (Mpk1p). Column retention experiments using wild-type and mutant forms of Hsp90 and Slt2p MAP kinase, as well as quantitative measurements of the effects of stress on the two-hybrid interaction of mutant Hsp90-BD and AD-Slt2p fusions, revealed that Hsp90 binds exclusively to the dually Thr/Tyr-phosphorylated, stress-activated form of Slt2p [(Y-P,T-P)Slt2p] and also to the MAP kinase domain within this (Y-P,T-P)Slt2p. Phenotypic analysis of a yeast mutant that expresses a mutant Hsp90 (T22Ihsp82) revealed that Hsp90 function is essential for this (Y-P,T-P)Slt2p to activate one of its downstream targets, the Rlm1p transcription factor. The interaction between Hsp90 and (Y-P,T-P)Slt2p, characterized in this study, is probably essential in this Hsp90 facilitation of the Rlm1p activation by Slt2p.

Caffeine↗
PubMed2006

Novel targets for antithrombotic drug discovery.

Platelet aggregation is a dynamic entity, capable of directing its own growth and stability via the activation of signaling cascades that lead to the expression and secretion of various secondary agonists. Recent data using proteomics and genomics strategies have established that signaling pathways during platelet aggregation are triggered by two homophilic adhesion molecules, CD84 and CD150 (SLAM), and by a novel EGF-containing receptor, PEAR1, which are tyrosine-phosphorylated in a platelet-aggregation-dependent fashion (N. Nanda, P. Andre, M. Bao et al., Platelet aggregation induces platelet aggregate stability via SLAM family receptor signaling, Blood 106 (2005) 3028-3034, N. Nanda, M. Bao, H. Lin et al., Platelet Endothelial Aggregation Receptor 1 (PEAR1), a novel epidermal growth factor repeat-containing transmembrane receptor, participates in platelet contact-induced activation, J. Biol. Chem. 280 (2005) 24680-24689). Analysis of SLAM-deficient mice revealed an overall defect in platelet aggregation in vitro and a delayed arterial thrombotic process in vivo. The data indicate that these aggregation co-receptors may function in a "platelet synapse" and may be novel targets for antithrombotic drug discovery.

Animals↗
PubMedDate not supplied

Method for qualitative comparisons of protein mixtures based on enzyme-catalyzed stable-isotope incorporation.

Determining which proteins are unique among one or several protein populations is an often-encountered task in proteomics. To this purpose, we present a new method based on trypsin-catalyzed incorporation of the stabile isotope (18)O in the C-termini of tryptic peptides, followed by LC-MALDI MS analysis. The analytical strategy was designed such that proteins unique to a given population out of several can be assigned in a single experiment by the isotopic signal intensity distributions of their tryptic peptides in the recorded mass spectra. The method is demonstrated for protein-protein interaction analysis, in which the differential isotope labeling was used to distinguish endogenous human brain proteins interacting with a recombinant bait protein from nonbiospecific background binders.

Brain↗
PubMed2005

Proteomic and transcriptomic analyses of macrophages with an increased resistance to oxidized low density lipoprotein (oxLDL)-induced cytotoxicity generated by chronic exposure to oxLDL.

The uptake of oxidized low density lipoprotein (oxLDL) by macrophages leads to foam cell formation and fatty streaks, which represent early sites of potential atheroma development. We developed a cell culture model of chronic oxLDL exposure to determine whether hallmark parameters of oxLDL uptake and cytotoxicity are altered during foam cell formation and to determine changes in protein and mRNA expression that distinguish acute and chronic oxLDL exposure. Although the extent of oxLDL uptake did not change, a resistance to oxLDL-induced cytotoxicity was observed in the chronically exposed cells. Macrophages that have been chronically exposed to oxLDL required a 40% higher concentration of oxLDL to achieve 50% survival in a 48-h treatment relative to macrophages subjected to a single oxLDL exposure. A main feature of the differentially expressed proteome was a series of significantly overexpressed antioxidant and antioxidant-related proteins in the oxLDL-exposed cells. A large proportion of these proteins (45%) was overexpressed in the chronically exposed cells prior to the oxLDL treatment, indicative of the unique phenotype produced by the chronic treatment. Analysis of the transcriptome also revealed a broad increase in the expression of antioxidant and antioxidant-related proteins. In addition, the transcriptome experiments found an increased inflammatory response under conditions of both acute and chronic oxLDL exposure. Overall the combined functional, proteomic, and transcriptomic experiments show that macrophages respond to oxLDL by developing an oxidative stress resistance that increases and stabilizes with chronic exposure. Furthermore this protective response and the increased foam cell survival that it supports amplifies their proatherogenic role by promoting a continued inflammatory state.

Animals↗
PubMed2003

Antigenic properties of HpaA and Omp18, two outer membrane proteins of Helicobacter pylori.

Outer membrane proteins (OMPs) are incorporated into the outer plasma membrane of Helicobacter pylori and are important for, e.g., ion transport, adherence, structural and osmotic stability, and bacterial virulence but may also be antigenic due to their surface exposure. Previous proteome-based approaches with H. pylori lysates determined a strong serological reaction towards two H. pylori OMPs, HpaA (TIGR HP0797) and Omp18 (TIGR HP1125). PCR was used to detect DNA encoding the two proteins, and a positive signal was found in all H. pylori strains tested. Proteins were cloned and expressed in the human kidney cell line HK293 with the QiaExpressionist system with a C-terminal His tag. Only sera from infected persons showed a positive reaction with the recombinant proteins. Recombinant HpaA (rHpaA) and rOmp18 were incubated with human peripheral blood mononuclear cells and induced secretion of interleukin-12 (IL-12) and IL-10 from these cells. To determine the effect on antigen-presenting cells, human blood monocytic and dendritic cells (DCs) were isolated by magnetic cell separation. rOmp18 and rHpaA strongly stimulated major histocompatibility class II and CD83 expression 7- to 10-fold on isolated DCs. rHpaA and rOmp18 failed to stimulate IL-8 secretion from monocytes but increased secretion of IL-12 and IL-10 from DCs significantly. In summary, HpaA and Omp18 are recognized by human dendritic cells and induce their maturation as well as antigen presentation. HpaA and Omp18 of H. pylori thereby appear to have a specific antigenic potential in humans.

Adhesins, Bacterial↗
PubMed2004

In vitro biomarker discovery for atherosclerosis by proteomics.

The purpose of this study was to identify in vitro and then prioritize a tractable set of protein biomarker candidates of atherosclerosis that may eventually be developed to measure the extent, progression, regression, and stability of atherosclerotic lesions. A study was conducted using an in vitro"foam cell" model based on the stimulation of differentiated THP1 cells with oxidized low-density lipoprotein (oxidized LDL) as compared with low-density lipoprotein (LDL). Analysis of the proteins contained in the cell supernatant using proteome scanning technology identified 59 proteins as being increased, 57 with no statistically measurable difference, and 17 decreasing in abundance following treatment with oxidized LDL, as compared with LDL. From the up-regulated list, proteins were prioritized based on their analytical confidence as well as their relevance to atherosclerosis pathways. Within the group of increased abundance, seven families of proteins were of particular interest: fatty acid-binding proteins, chitinase-like enzymes, cyclophilins, cathepsins, proteoglycans, urokinase-type plasminogen activator receptor, and a macrophage scavenger receptor.

Amino Acid Sequence↗
PubMed2002

Bacillus subtilis functional genomics: genome-wide analysis of the DegS-DegU regulon by transcriptomics and proteomics.

The DegS-DegU two-component regulatory system of Bacillus subtilis controls various processes that characterize the transition from the exponential to the stationary growth phase, including the induction of extracellular degradative enzymes, expression of late competence genes and down-regulation of the sigma(D) regulon. The degU32(Hy) mutation stabilizes the phosphorylated form of DegU (DegU-P), resulting in overproduction of several extracellular degradative enzymes. In this study, the pleiotropic DegS-DegU regulon was characterized by combining proteomic and transcriptomic approaches. A comparative analysis of wild-type B. subtilis and the degU32(Hy) mutant grown in complex medium was performed during the exponential and in the stationary growth phase. Besides genes already known to be under the control of DegU-P, novel putative members of this regulon were identified. Although the degU32(Hy) mutant is assumed to contain high levels of phosphorylated DegU in the exponential as well as in the stationary growth phase, many genes known to be positively regulated by DegU-P did not show enhanced expression in the mutant strain during exponential growth. This is consistent with the fact that most genes belonging to the DegS-DegU regulon are subject to multiple regulation; this is also reflected in the strong stationary-phase induction of these genes in the mutant strain. As expected, during the exponential growth phase, the sigma(D) regulon was expressed at significantly lower levels in the degU32(Hy) mutant than in the wild type.

Bacillus subtilis↗
PubMed2001

Bacterial cell cycle: seeing the big picture with microarrays.

Global assays of gene expression and protein stability during the Caulobacter crescentus cell cycle reveal that a surprisingly large fraction of the genome and proteome is affected as cells grow and divide. These studies are an important step toward understanding how the cell cycle is controlled in prokaryotes.

Bacterial Proteins↗