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PubMed2000

Proteomic analysis of two functional states of the Golgi complex in mammary epithelial cells.

Organellar compartments involved in secretion are expanded during the transition from late pregnancy (basal secretory state) to lactation (maximal secretory state) to accommodate for the increased secretory function required for copious milk production in mammary epithelial cells. The Golgi complex is a major organelle of the secretory pathway and functions to sort, package, distribute, and post-translationally modify newly synthesized proteins and membrane lipids. These complex functions of the Golgi are reflected in the protein complement of the organelle. Therefore, using proteomics, the protein complements of Golgi fractions isolated at two functional states (basal and maximal) were compared to identify some of the molecular changes that occur during this transition. This global analysis has revealed that only a subset of the total proteins is upregulated from steady state during the transition. Identification of these proteins by tandem mass spectrometry has revealed several classes of proteins involved in the regulation of membrane fusion and secretion. This first installment of the functional proteomic analysis of the Golgi complex begins to define the molecular basis for the transition from basal to maximal secretion.

Animals↗
PubMed2004

In-depth analysis of the thylakoid membrane proteome of Arabidopsis thaliana chloroplasts: new proteins, new functions, and a plastid proteome database.

An extensive analysis of the Arabidopsis thaliana peripheral and integral thylakoid membrane proteome was performed by sequential extractions with salt, detergent, and organic solvents, followed by multidimensional protein separation steps (reverse-phase HPLC and one- and two-dimensional electrophoresis gels), different enzymatic and nonenzymatic protein cleavage techniques, mass spectrometry, and bioinformatics. Altogether, 154 proteins were identified, of which 76 (49%) were alpha-helical integral membrane proteins. Twenty-seven new proteins without known function but with predicted chloroplast transit peptides were identified, of which 17 (63%) are integral membrane proteins. These new proteins, likely important in thylakoid biogenesis, include two rubredoxins, a potential metallochaperone, and a new DnaJ-like protein. The data were integrated with our analysis of the lumenal-enriched proteome. We identified 83 out of 100 known proteins of the thylakoid localized photosynthetic apparatus, including several new paralogues and some 20 proteins involved in protein insertion, assembly, folding, or proteolysis. An additional 16 proteins are involved in translation, demonstrating that the thylakoid membrane surface is an important site for protein synthesis. The high coverage of the photosynthetic apparatus and the identification of known hydrophobic proteins with low expression levels, such as cpSecE, Ohp1, and Ohp2, indicate an excellent dynamic resolution of the analysis. The sequential extraction process proved very helpful to validate transmembrane prediction. Our data also were cross-correlated to chloroplast subproteome analyses by other laboratories. All data are deposited in a new curated plastid proteome database (PPDB) with multiple search functions (http://cbsusrv01.tc.cornell.edu/users/ppdb/). This PPDB will serve as an expandable resource for the plant community.

Amino Acid Sequence↗
PubMed2003

Functional genomics and proteomics as a foundation for systems biology.

Developments in high-throughput measurement technologies for biological molecules have created a paradigm shift in modern life science research. The field of systems biology attempts to provide a systems-level understanding by systematically organising the genomic, functional genomic and proteomic data obtained from genetic and environmental perturbations of interest and using the data to build a descriptive and mechanistic model of the biological phenomena. The goal is to build a mathematical framework with some predictive abilities. This review highlights the need for system-level understanding, lists some of the high-throughput measurement tools of importance in systems biology, reviews various types of experimental and computational approaches being used in systems biology research and attempts to address some of the challenges facing this research community.

Animals↗
PubMed2006

Analyzing proteomes and protein function using graphical comparative analysis of tandem mass spectrometry results.

Although generating large amounts of proteomic data using tandem mass spectrometry has become routine, there is currently no single set of comprehensive tools for the rigorous analysis of tandem mass spectrometry results given the large variety of possible experimental aims. Currently available applications are typically designed for displaying proteins and posttranslational modifications from the point of view of the mass spectrometrist and are not versatile enough to allow investigators to develop biological models of protein function, protein structure, or cell state. In addition, storage and dissemination of mass spectrometry-based proteomic data are problems facing the scientific community. To address these issues, we have developed a relational database model that efficiently stores and manages large amounts of tandem mass spectrometry results. We have developed an integrated suite of multifunctional analysis software for interpreting, comparing, and displaying these results. Our system, Bioinformatic Graphical Comparative Analysis Tools (BIGCAT), allows sophisticated analysis of tandem mass spectrometry results in a biologically intuitive format and provides a solution to many data storage and dissemination issues.

Amino Acid Sequence↗
PubMed2003

Functional genomics and proteomics: charting a multidimensional map of the yeast cell.

The challenge of large-scale functional genomics projects is to build a comprehensive map of the cell including genome sequence and gene expression data, information on protein localization, structure, function and expression, post-translational modifications, molecular and genetic interactions and phenotypic descriptions. Some of this broad set of functional genomics data has been already assembled for the budding yeast. Even though molecular cartography of the yeast cell is still far from comprehensive, functional genomics has begun to forge connections between disparate cellular events and to foster numerous hypotheses. Here we review several different genomics and proteomics technologies and describe bioinformatics methods for exploring these data to make new discoveries.

Chromosome Mapping↗
PubMed2003

Identification of metastasis-associated proteins by proteomic analysis and functional exploration of interleukin-18 in metastasis.

Very little is currently known about mechanisms underlying cancer metastasis. In the present study, metastasis-associated proteomes were separated and identified by comparative proteomic analysis, and the metastasis-related function of candidate protein interleukin-18 (IL-18) was further elucidated. First, a pair of highly and poorly metastatic sublines (termed PLA801D and PLA801C, respectively), originating from the same parental PLA801 cell line, was identified by spontaneous tumorigenicity and metastasis in vivo and characterized by metastatic phenotypes analysis in vitro. Subsequently, a proteomic approach was used to compare the protein expression profiles between PLA801C and PLA801D sublines. Eleven proteins were identified and further verified by one-dimensional Western blotting, Northern blot and/or semiquantitative reverse transciptase polymerase chain reaction analysis. Compared with those in poorly metastatic PLA801C subline, cytokeratin 18, tissue transglutaminase, Rho GDP-dissociation inhibitor 1, tropomyosin, fibroblast type, IL-18 and annexin I were significantly up-regulated, while protein disulfide isomerase, heat shock protein 60, peroxiredoxin 1, chlorine intracellular channel protein 1 (CLI1) and creatine kinase, B chain were significantly down-regulated in the highly metastatic PLA801D subline. Intriguingly, all the identified candidate proteins except for CLI1 have been shown to be somehow associated with distinct aspects of tumor metastasis such as cell growth, motility, invasion, adhesion, apoptosis and tumor immunity, etc. Considering that IL-18 was present in highly metastatic PLA801D but absent in poorly metastatic PLA801C, the association of IL-18 with metastasis was further elucidated by introducing IL-18 sense/IL-18 antisense into PLA801C/PLA801D sublines simultaneously. The results demonstrated that ectopically expressed IL-18 promoted cell motility in vitro and down-regulated E-cadherin expression of PLA801C transfectants, while IL-18 antisense remarkably decreased cell invasion potency in vitro and notably increased E-cadherin expression of PLA801D transfectants, indicating that IL-18 might play a role in metastasis by inhibiting E-cadherin expression.

Animals↗
PubMed2002

Functional annotation of proteomic sequences based on consensus of sequence and structural analysis.

To maximise the assignment of function of the proteins encoded by a genome and to aid the search for novel drug targets, there is an emerging need for sensitive methods of predicting protein function on a genome-wide basis. GeneAtlas is an automated, high-throughput pipeline for the prediction of protein structure and function using sequence similarity detection, homology modelling and fold recognition methods. GeneAtlas is described in detail here. To test GeneAtlas, a 'virtual' genome was used, a subset of PDB structures from the SCOP database, in which the functional relationships are known. GeneAtlas detects additional relationships by building 3D models in comparison with the sequence searching method PSI-BLAST. Functionally related proteins with sequence identity below the twilight zone can be recognised correctly.

Consensus Sequence↗
PubMed2003

Transposon-based strategies for microbial functional genomics and proteomics.

Transposons are mobile genetic elements that can relocate from one genomic location to another. As well as modulating gene expression and contributing to genome plasticity and evolution, transposons are remarkably diverse molecular tools for both whole-genome and single-gene studies in bacteria, yeast, and other microorganisms. Efficient but simple in vitro transposition reactions now allow the mutational analysis of previously recalcitrant microorganisms. Transposon-based signature-tagged mutagenesis and genetic footprinting strategies have pinpointed essential genes and genes that are crucial for the infectivity of a variety of human and other pathogens. Individual proteins and protein complexes can be dissected by transposon-mediated scanning linker mutagenesis. These and other transposon-based approaches have reaffirmed the usefulness of these elements as simple yet highly effective mutagens for both functional genomic and proteomic studies of microorganisms.

Artificial Gene Fusion↗
PubMed2006

LC-MS/MS based proteomic analysis and functional inference of hypothetical proteins in Desulfovibrio vulgaris.

High efficiency capillary liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to examine the proteins extracted from Desulfovibrio vulgaris cells across six treatment conditions. While our previous study provided a proteomic overview of the cellular metabolism based on proteins with known functions [W. Zhang, M.A. Gritsenko, R.J. Moore, D.E. Culley, L. Nie, K. Petritis, E.F. Strittmatter, D.G. Camp II, R.D. Smith, F.J. Brockman, A proteomic view of the metabolism in Desulfovibrio vulgaris determined by liquid chromatography coupled with tandem mass spectrometry, Proteomics 6 (2006) 4286-4299], this study describes the global detection and functional inference for hypothetical D. vulgaris proteins. Using criteria that a given peptide of a protein is identified from at least two out of three independent LC-MS/MS measurements and that for any protein at least two different peptides are identified among the three measurements, 129 open reading frames (ORFs) originally annotated as hypothetical proteins were found to encode expressed proteins. Functional inference for the conserved hypothetical proteins was performed by a combination of several non-homology based methods: genomic context analysis, phylogenomic profiling, and analysis of a combination of experimental information, including peptide detection in cells grown under specific culture conditions and cellular location of the proteins. Using this approach we were able to assign possible functions to 20 conserved hypothetical proteins. This study demonstrated that a combination of proteomics and bioinformatics methodologies can provide verification of the expression of hypothetical proteins and improve genome annotation.

Amino Acid Sequence↗
PubMed2004

Redox proteomics: identification and functional role of glutathionylated proteins.

Although radical oxygen and nitrogen species are harmful molecules that destroy cell functions, many operate as mediators of important cell signaling pathways when not in excess. Oxidants can modify protein function through the covalent, reversible addition of glutathione to cysteine. This review addresses different proteomic methods of identifying glutathionylation targets and emphasizes ways of defining their pattern of modification in response to oxidative stimuli in cells. Finally, the literature on nonproteomic studies that investigate the functional changes induced by glutathionylation are reviewed and future studies are commented on.

Animals↗
PubMed2006

Identification of metastasis candidate proteins among HCC cell lines by comparative proteome and biological function analysis of S100A4 in metastasis in vitro.

Widespread metastasis of hepatocellular carcinoma (HCC) was a complex cascade of events, which is still beyond full appreciation. Screening key proteins, which play a critical role in metastasis, using high-throughput proteomics approach help discover valuable biomarkers and elucidate the mechanism of metastasis. This study was to find out some metastasis candidate proteins among HCC cell lines with various metastatic potential by comparative proteomics, and then further validate the biological function of these proteins in metastasis in vitro. The protein profiles of metastatic HCC cell lines (MHCC97H and MHCC97L) displayed obvious differences compared with nonmetastatic ones (Hep3B). Twenty-six metastasis candidate proteins, which were identified by on-line LC-ESI-MS/MS, such as S100 calcium-binding protein A4 (S100A4), annexin 1, etc., might have much application in diagnostic procedures and prognosis evaluation. S100A4, as a leading different metastasis candidate protein, which overexpressed only in the metastatic cells, was selected for further investigation. A series of assays related to invasion and metastasis in vitro, including cell motility, invasion, and matrix metalloproteinases (MMPs) secretion, were performed in MHCC97H/antisense recombinant plasmid to S100A4 (pcDNA3.1(+) AS S100A4) and the mock controls. All the data in the present study suggested that S100A4 might contribute to HCC invasion and metastasis through two paths of matrix metalloproteinase (MMP9) secretion regulation and strengthened motility and invasion properties.

Apoptosis↗
PubMed2025

Long COVID in Elderly COPD Patients: Clinical Features, Pulmonary Function Decline, and Proteomic Insights.

BACKGROUND: Elderly patients with chronic obstructive pulmonary disease (COPD) face a heightened risk of developing long coronavirus disease (COVID); however the exact clinical characteristics and underlying mechanisms remain unclear. METHODS: We enrolled 85 elderly COPD patients, of whom 43 reported newly onset persistent fatigue (the most dominant complaint of long COVID) within 1 year after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, and they were allocated to the Long-COVID group. The remaining 42 patients were assigned to the Control group. Patients completed questionnaires, pulmonary function tests, chest CT, routine laboratory tests, and blood proteomic analysis. RESULTS: Long-COVID patients had a longer course of COPD (> 5 years, 76.8% vs 52.4%) and duration of SARS-CoV-2 infection (10.0 days vs 7.0 days) (All P < 0.05), higher symptom burden, worse pulmonary ventilation function and a more rapid decrease in DLCO (All P < 0.05). Proteomic analysis indicated disruptions in inflammation and energy metabolism, potentially underlying long COVID in these patients. The machine learning model identified wheezing, the duration of SARS-CoV-2 infection, EIF2S3 (eukaryotic translation initiation factor 2 subunit gamma), current FEV1/FVC (%), and the course of COPD as key features distinguishing Long-COVID patients, and exhibited excellent performance. CONCLUSION: Elderly COPD patients with a longer COPD course and duration of COVID-19 are more prone to develop long COVID, with decreased pulmonary ventilation and diffusion ability. Disordered inflammation regulation and energy metabolism may be the potential mechanisms, highlighting the importance of monitoring inflammation and metabolic dysregulation in elderly COPD patients after recovery from COVID-19.

Humans↗
PubMed1999

Classifying symbiotic proteins from Bradyrhizobium japonicum into functional groups by proteome analysis of altered gene expression levels.

The advent of whole genome sequences has brought with it a vast number of new potential proteins whose function is unknown. We describe an approach to sorting proteins into functional groups by comparative two-dimensional (2-D) gel mapping of cells grown under different physiological conditions. Computerized image analysis selects the proteins whose expression levels change significantly for subsequent identification by mass spectrometry. The protein groupings are further subdivided by directed alteration of their expression levels (e.g., by gene inactivation) and following the changes in the expression pattern of the mutants. We have applied this approach to study the regulation of micro- and anaerobically induced genes including the genes involved in nitrogen fixation in the symbiotic bacterium Bradyrhizobium japonicum. The results obtained show that in addition to the two known regulons controlled by the transcription factors NifA and FixK2, a third set of proteins may exist in B. japonicum which are induced by anaerobic conditions and are regulated independently. The approach can be applied generally and can be used to build up functional relationship maps of genomes. Protein identification by mass spectrometry was shown to be vital to the interpretation of the expression analysis since 15% of the 2-D gel spots contained more than one protein.

Amino Acid Sequence↗
PubMed2004

Functional genomics and proteomics: application in neurosciences.

The sequencing of the complete genome for many organisms, including man, has opened the door to the systematic understanding of how complex structures such as the brain integrate and function, not only in health but also in disease. This blueprint, however, means that the piecemeal analysis regimes of the past are being rapidly superseded by new methods that analyse not just tens of genes or proteins at any one time, but thousands, if not the entire repertoire of a cell population or tissue under investigation. Using the most appropriate method of analysis to maximise the available data therefore becomes vital if a complete picture is to be obtained of how a system or individual cell is affected by a treatment or disease. This review examines what methods are currently available for the large scale analysis of gene and protein expression, and what are their limitations.

Brain↗
PubMed2001

FLEXGene repository: from sequenced genomes to gene repositories for high-throughput functional biology and proteomics.

The vast amount of information generated by the human genome sequencing project and related projects has given rise to a new paradigm in experimental biology. This new paradigm invokes the experimentation and data analysis at genome-wide scales, as well as the generation of new technologies and resources that take full advantage of the available sequence information. The Institute of Proteomics at Harvard Medical School is building a comprehensive, characterized, arrayed and flexible gene repository that will allow full exploitation of the genomic information by enabling functional genomics as well as protein expression, purification and analysis at genome wide scale. The FLEXGene repository (Full Length EXpression-ready) will contain clones representing the complete set of open reading frames (ORFs) of different organisms including H. sapiens and several pathogens and model organisms. The clones are constructed using recombination-based cloning technology so that hundreds or thousands of coding regions can be transferred into any expression vector in a parallel and timely mode, allowing the broadest variety of experiments to be carried out.

Animals↗
PubMed2002

Bioinformatics, functional genomics, and proteomics study of Bacillus sp.

The ability of bioinformatics to characterize genomic and proteomic sequences from bacteria Bacillus sp. for prediction of genes and proteins has been evaluated. Genomics coupling with proteomics, which is relied on integration of the significant advances recently achieved in two-dimensional (2-D) electrophoretic separation of proteins and mass spectrometry (MS), are now important and high throughput techniques for qualifying and analyzing gene and protein expression, discovering new gene or protein products, and understanding of gene and protein functions including post-genomic study. In addition, the bioinformatics of Bacillus sp. is embraced into many databases that will facilitate to rapidly search the information of Bacillus sp. in both genomics and proteomics. It is also possible to highlight sites for post-translational modifications based on the specific protein sequence motifs that play important roles in the structure, activity and compartmentalization of proteins. Moreover, the secreted proteins from Bacillus sp. are interesting and widely used in many applications especially biomedical applications that are the highly advantages for their potential therapeutic values.

Bacillus↗