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PubMed2006

Integrative proteomics: structure, function, and interaction report on the 3rd joint meeting of the British Society for Proteome Research and the European Bioinformatics Institute, July 2006.

This report summarizes the highlights of the recent British Society for Proteome Research (BSPR) meeting jointly organized with the European Bioinformatics Institute (EBI) which was held at the Wellcome Trust Genome Campus, Hinxton, Cambridge, UK in July 2006. This was the third annual scientific meeting organized by the BSPR and EBI and the theme of this years meeting was Integrative Proteomics: Structure, function and interaction. A wealth of local and overseas speakers were invited to discuss both their own work and specific challenges present in modern day proteomic based experiments.

Computational Biology↗
PubMedDate not supplied

Implications of new proteomics strategies for biology and medicine.

Advances in proteomics have fundamentally changed the paradigm of discovery for drug targets and novel biomarkers. Proteomics methodologies currently used will be reviewed in this paper, including structural proteomics, quantitative proteomics, and functional proteomics. A strategy to identify differentially expressed cell surface proteins as monoclonal therapeutic targets in oncology will be discussed.

Biology↗
PubMed2003

Pharmacoproteomics in drug development.

The field of proteomics is taking on increased significance as the relevance of investigating and understanding protein expression in disease and drug development is appreciated. Recent advances in proteomics have been driven by the availability of numerous annotated whole-genome sequences and a broad range of technological and bioinformatic developments that underscore the complexity of the proteome. This review briefly addresses some of the various technologies that comprise Expression Proteomics and Functional Proteomics, citing examples where these emerging approaches have been applied to pharmacology, toxicology, and the development of drugs.

Animals↗
PubMed2003

[Proteomics-based identification of Maspin differential expression in bronchial epithelial immortalized cells and malignant transformation cells].

BACKGROUND & OBJECTIVE: Maspin, a serepin inhibitor, plays a key role in tumor growth and metastasis. The aim of this study was to identify the differential expression of Maspin in malignant transformation process of bronchial epithelial cells by proteomics. METHODS: Functional proteomics analysis of Maspin on bronchial epithelial immortalized cells and malignant transformation cells was carried out using immobilized pH gradient (IPG) two-dimensional electrophoresis, peptide mass fingerprinting (PMF), and post source decay (PSD) of bio-mass spectrometry. RESULTS: Nearly 1500 expressed proteins profile on bronchial epithelial immortalized cells and malignant transformation cells were obtained in the range of MW 14.4-94 kDa, PI 3-10. Image analysis showed that Maspin was down-regulated in malignant transformation cells compared with that in immortalized cells. Northern blot analysis showed that the mRNA abundance of Maspin in malignant transformation cells was much lower than that in immortalized cells. CONCLUSION: Alteration expression of Maspin at transcription and translation levels might be involved in carcinogenesis of lung.

Blotting, Northern↗
PubMed2005

Practical cancer genetics, genomics and proteomics.

Functional genomics is the science that defines the function of newly identified genes and translates this knowledge into related health and disease. Functional genomics is complex, involving multiple scientific disciplines including computational biology, genetics, physiology, structural biology, and molecular and cell biology. Due to its inherent complexity, the National Institutes of Health (NIH) has termed functional genomics "the science of collaboration." This paper will review microarray gene expression analysis, proteomics, and the impact of molecular medical genetics on medical care.

Gene Expression↗
PubMed2002

Growth signaling in breast cancer cells: outcomes and promises of proteomics.

Methods in functional proteomics are now used to study the intracellular signaling pathways that underlie the development of breast cancer. As shown with fibroblast growth factor-2, the oncogenic/non-coding mRNA H19 and 14-3-3 proteins, proteomics is a powerful approach to identify signaling proteins and to decipher the complex signaling circuitry involved in growth of breast cancer cells. Together with genomics, proteomics is now providing a way to define molecular processes involved in breast cancerogenesis and to identify new therapeutic targets.

14-3-3 Proteins↗
PubMedDate not supplied

Prospective highlights of functional skin proteomics.

Although a wide variety of protein profiles have been extensively constructed via proteomic analysis, the comprehensive proteomic profiling of the skin, which is considered to be the largest organ of the human body, is still far from complete. Our efforts to establish the functional skin proteome, a protein database describing the protein networks that underlie biological processes, has set in motion the identification and characterization of proteins expressed in the epidermis and dermis of the BALB/c mice. In this review, we will highlight various cutaneous proteins we have characterized and discuss their biological functions associated with skin distress, immunity, and cancer. This type of research into functional skin proteomics will provide a critical step toward understanding disease and developing successful therapeutic strategies.

Animals↗
PubMed2002

Molecular biologist's guide to proteomics.

The emergence of proteomics, the large-scale analysis of proteins, has been inspired by the realization that the final product of a gene is inherently more complex and closer to function than the gene itself. Shortfalls in the ability of bioinformatics to predict both the existence and function of genes have also illustrated the need for protein analysis. Moreover, only through the study of proteins can posttranslational modifications be determined, which can profoundly affect protein function. Proteomics has been enabled by the accumulation of both DNA and protein sequence databases, improvements in mass spectrometry, and the development of computer algorithms for database searching. In this review, we describe why proteomics is important, how it is conducted, and how it can be applied to complement other existing technologies. We conclude that currently, the most practical application of proteomics is the analysis of target proteins as opposed to entire proteomes. This type of proteomics, referred to as functional proteomics, is always driven by a specific biological question. In this way, protein identification and characterization has a meaningful outcome. We discuss some of the advantages of a functional proteomics approach and provide examples of how different methodologies can be utilized to address a wide variety of biological problems.

Amino Acid Sequence↗
PubMed2002

Dynamics of protein turnover, a missing dimension in proteomics.

Functional genomic experiments frequently involve a comparison of the levels of gene expression between two or more genetic, developmental, or physiological states. Such comparisons can be carried out at either the RNA (transcriptome) or protein (proteome) level, but there is often a lack of congruence between parallel analyses using these two approaches. To fully interpret protein abundance data from proteomic experiments, it is necessary to understand the contributions made by the opposing processes of synthesis and degradation to the transition between the states compared. Thus, there is a need for reliable methods to determine the rates of turnover of individual proteins at amounts comparable to those obtained in proteomic experiments. Here, we show that stable isotope-labeled amino acids can be used to define the rate of breakdown of individual proteins by inspection of mass shifts in tryptic fragments. The approach has been applied to an analysis of abundant proteins in glucose-limited yeast cells grown in aerobic chemostat culture at steady state. The average rate of degradation of 50 proteins was 2.2%/h, although some proteins were turned over at imperceptible rates, and others had degradation rates of almost 10%/h. This range of values suggests that protein turnover is a significant missing dimension in proteomic experiments and needs to be considered when assessing protein abundance data and comparing it to the relative abundance of cognate mRNA species.

Amino Acids↗
PubMed2003

Integrating proteomic and functional genomic technologies in discovery-driven translational breast cancer research.

The application of state-of-the-art proteomics and functional genomics technologies to the study of cancer is rapidly shifting toward the analysis of clinically relevant samples derived from patients, as the ultimate aim of translational research is to bring basic discoveries closer to the bedside. Here we describe the essence of a long-term initiative undertaken by The Danish Centre for Translational Breast Cancer Research and currently underway for cancer biomarker discovery using fresh tissue biopsies and bio-fluids. The Centre is a virtual hub that brings together scientists working in various areas of basic cancer research such as cell cycle control, invasion and micro-environmental alterations, apoptosis, cell signaling, and immunology, with clinicians (oncologists, surgeons), pathologists, and epidemiologists, with the aim of understanding the molecular mechanisms underlying breast cancer progression and ultimately of improving patient survival and quality of life. The unifying concept behind our approach is the use of various experimental paradigms for the prospective analysis of clinically relevant samples obtained from the same patient, along with the systematic integration of the biological and clinical data.

Academies and Institutes↗
PubMed2002

Disulfide proteome in the analysis of protein function and structure.

Many proteins undergo post-translational modification via well defined mechanisms such as acetylation, phosphorylation and glycosylation and thereby control a spectrum of biochemical processes. A growing body of evidence suggests that the reversible reduction of disulfide bonds also alters the structure and activity of proteins. Thioredoxin, a ubiquitous 12 kDa protein with a catalytically active disulfide active site (Cys-Gly-Pro-Cys), plays a central role in controlling the redox status of disulfide bonds in proteins that regulate a range of processes. Included are photosynthesis, seed germination, transcription, cell division, radical scavenging and detoxification. The ability to identify unknown functions of proteins of all types has been advanced by the emerging field of functional proteomics. In this brief review, we introduce the disulfide proteome as a tool that complements other methods for the comprehensive analysis of proteins. In so doing, the usefulness of applying this method for both in vitro and in vivo analyses is discussed for thioredoxin and other disulfide proteins, especially those occurring in plants.

Allergens↗
PubMed2005

Proteomic and functional analyses reveal a mitochondrial dysfunction in P301L tau transgenic mice.

Transgenic mice overexpressing the P301L mutant human tau protein exhibit an accumulation of hyperphosphorylated tau and develop neurofibrillary tangles. The consequences of tau pathology were investigated here by proteomics followed by functional analysis. Mainly metabolism-related proteins including mitochondrial respiratory chain complex components, antioxidant enzymes, and synaptic proteins were identified as modified in the proteome pattern of P301L tau mice. Significantly, the reduction in mitochondrial complex V levels in the P301L tau mice revealed using proteomics was also confirmed as decreased in human P301L FTDP-17 (frontotemporal dementia with parkinsonism linked to chromosome 17) brains. Functional analysis demonstrated a mitochondrial dysfunction in P301L tau mice together with reduced NADH-ubiquinone oxidoreductase activity and, with age, impaired mitochondrial respiration and ATP synthesis. Mitochondrial dys-function was associated with higher levels of reactive oxygen species in aged transgenic mice. Increased tau pathology as in aged homozygous P301L tau mice revealed modified lipid peroxidation levels and the up-regulation of antioxidant enzymes in response to oxidative stress. Furthermore, P301L tau mitochondria displayed increased vulnerability toward beta-amyloid (Abeta) peptide insult, suggesting a synergistic action of tau and Abeta pathology on the mitochondria. Taken together, we conclude that tau pathology involves a mitochondrial and oxidative stress disorder possibly distinct from that caused by Abeta.

Alzheimer Disease↗
PubMed2006

Integrating forward and reverse proteomics to unravel protein function.

To date, proteomics approaches have aimed to either identify novel proteins or change in protein expression/modification in various organisms under normal or disease conditions. One major aspect of functional proteomics is to identify protein biological properties in a given context, however, forward proteomics approaches alone cannot complete this goal. Indeed, with the increasing successes of such proteomics-based research strategies and the subsequent increasing amounts of proteins identified with unknown molecular functions, approaches allowing for systematic analyses of protein functions are desired. In this review, we propose to depict the complementarities of forward and reverse proteomics approaches in the definite understanding of protein functions. This dual strategy requires a data integration loop which allows for systematic characterization of protein function(s). The details of the integrative process combining both in silico and experimental resources and tools are presented. Altogether, we believe that the integration of forward and reverse proteomics approaches supported by bioinformatics will provide an efficient path towards systems biology.

Animals↗
PubMed2026

Functional and Proteomic Profiles of CD3(+) Plasma-Derived Small Extracellular Vesicles Differentiate Cancer Patients From Healthy Donors.

Small extracellular vesicles (sEV) released by T cells play a key role in immune regulation. Immune capture with anti-CD3 antibodies was used to isolate and study T cell-derived CD3(+)sEV from the plasma of patients with melanoma (MPs) or healthy donors (HDs). Functional responses induced in recipient target cells by CD3(+)sEV of MPs differed from responses induced by CD3(+)sEV of HDs. Approximating functions mediated by melanoma cell-derived sEV (MTEX), CD3(+)sEV of MPs reduced metabolic activity and proliferation of T cells while promoting activity in Mel526 cell targets. Proteomics profiling confirmed functional differences between CD3(+)sEV of MPs and HDs. Of 294 sEV-specific proteins identified in CD3(+)sEV, 226 were detected in the parent T cell proteome, confirming that the CD3(+)sEV proteome mimics that of the parent T lymphocytes. Among them were 66 differentially expressed proteins (DEPs) that differentiated vesicles from MPs and HDs. These DEPs were associated with processes linked to cancer-related functions. DEPs upregulated in CD3(+)sEV of MPs were associated with RHO-GTPase, cytokine, and MAPK signaling pathways. Thus, T cells of MPs were reprogrammed by MTEX to produce CD3(+)sEV that functionally resembled MTEX, partly recapitulated features of the tumor proteome, and differed from CD3(+)sEV of HDs. In cancer, the TEX-rewired T cells produce CD3(+)sEV that potentially could serve as a liquid biopsy of patients' T cells.

Humans↗
PubMed2004

Challenges in mass spectrometry-based proteomics.

During the last decade, protein analysis and proteomics have been established as new tools for understanding various biological problems. As the identification of proteins after classical separation techniques, such as two-dimensional gel electrophoresis, have become standard methods, new challenges arise in the field of proteomics. The development of "functional proteomics" combines functional characterization, like regulation, localization and modification, with the identification of proteins for deeper insight into cellular functions. Therefore, different mass spectrometric techniques for the analysis of post-translational modifications, such as phosphorylation and glycosylation, have been established as well as isolation and separation methods for the analysis of highly complex samples, e.g. protein complexes or cell organelles. Furthermore, quantification of protein levels within cells is becoming a focus of interest as mass spectrometric methods for relative or even absolute quantification have currently not been available. Protein or genome databases have been an essential part of protein identification up to now. Thus, de novo sequencing offers new possibilities in protein analytical studies of organisms not yet completely sequenced. The intention of this review is to provide a short overview about the current capabilities of protein analysis when addressing various biological problems.

Algorithms↗
PubMed2006

A new functional, chemical proteomics technology to identify purine nucleotide binding sites in complex proteomes.

Adenine nucleotides are small, abundant molecules that bind numerous proteins involved in pivotal cellular processes. These nucleotides are co-factors or substrates for enzymes, regulators of protein function, or structural binding motifs. The identification of nucleotide-binding sites on a proteome-wide scale is tempting in view of the high number of nucleotide-binding proteins, their large in vivo concentration differences, and the various functions they exert. Here, we report on a functional, chemical, gel-free proteomics technology that allows the identification of protein adenine nucleotide-binding site(s) in cell lysates. Our technology uses a synthetic ATP analogue, 5'-p-fluorosulfonylbenzoyladenosine (FSBA), as an affinity/activity-based probe for nucleotide-binding sites. When applied on a cellular level, 185 different FSBA-labeled sites in a human Jurkat cell lysate were identified. Functional and structural aspects of the use of FSBA on a proteome-wide scale are discussed.

Adenine↗
PubMed2005

The human platelet proteome mapped by peptide-centric proteomics: a functional protein profile.

Several studies have been published in which holistic approaches were used to characterise the proteome and transcriptome of human platelets. The key intent being that a deeper understanding of the normal and aberrant physiological functions of platelets can only be achieved if most biomolecular building blocks are mapped. Here we present the application of recently developed novel technologies that overcome some of the shortcomings of gel-based proteomics. Central in our approach is the so-called combined fractional diagonal chromatography (COFRADIC)-technology in which sets of representative peptides are sorted in a diagonal RP chromatographic system through a specific modification of their side chain. In this study we combined three different COFRADIC sorting techniques to analyse the proteome of human platelets. Methionyl, cysteinyl and amino terminal peptides were isolated and analysed by MS/MS. Merging the peptide identifications obtained after database searching resulted in a core set of 641 platelet proteins, which comprises the largest set identified today. In comparison to previously published platelet proteomes, we identified 404 novel platelet proteins containing a high number of hydrophobic membrane proteins and hypothetical proteins. Furthermore we discuss the observed characteristics and potential benefits of each of the different COFRADIC technologies for proteome analysis and highlight important issues that need to be considered when searching sequence databases using data obtained in peptide-centric, non-gel proteomics studies.

Animals↗
PubMed2006

The proteome: structure, function and evolution.

This paper reports two studies to model the inter-relationships between protein sequence, structure and function. First, an automated pipeline to provide a structural annotation of proteomes in the major genomes is described. The results are stored in a database at Imperial College, London (3D-GENOMICS) that can be accessed at www.sbg.bio.ic.ac.uk. Analysis of the assignments to structural superfamilies provides evolutionary insights. 3D-GENOMICS is being integrated with related proteome annotation data at University College London and the European Bioinformatics Institute in a project known as e-protein (http://www.e-protein.org/). The second topic is motivated by the developments in structural genomics projects in which the structure of a protein is determined prior to knowledge of its function. We have developed a new approach PHUNCTIONER that uses the gene ontology (GO) classification to supervise the extraction of the sequence signal responsible for protein function from a structure-based sequence alignment. Using GO we can obtain profiles for a range of specificities described in the ontology. In the region of low sequence similarity (around 15%), our method is more accurate than assignment from the closest structural homologue. The method is also able to identify the specific residues associated with the function of the protein family.

Computational Biology↗