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PubMed2006

Proteomic approaches to dissect platelet function: Half the story.

Platelets play critical roles in diverse hemostatic and pathologic disorders and are broadly implicated in various biological processes that include inflammation, wound healing, and thrombosis. Recent progress in high-throughput mRNA and protein profiling techniques has advanced our understanding of the biological functions of platelets. Platelet proteomics has been adopted to decode the complex processes that underlie platelet function by identifying novel platelet-expressed proteins, dissecting mechanisms of signal or metabolic pathways, and analyzing functional changes of the platelet proteome in normal and pathologic states. The integration of transcriptomics and proteomics, coupled with progress in bioinformatics, provides novel tools for dissecting platelet biology. In this review, we focus on current advances in platelet proteomic studies, with emphasis on the importance of parallel transcriptomic studies to optimally dissect platelet function. Applications of these global profiling approaches to investigate platelet genetic diseases and platelet-related disorders are also addressed.

Animals↗
PubMed2003

On the way to functional genomics.

Proteomics, the global comprehensive analysis of cellular proteins, will contribute to our understanding of gene function in the post-genomic era. The strategies of proteome analysis include the protein expression proteomics dealing with the comparison of cellular or tissue protein levels in the control and affected state (e.g. in the disease) and cell mapping proteomics aimed to define protein-protein interactions that constitute intracellular signalling network. The currently used methods of proteome analysis represent two-dimensional gel electrophoresis for protein separation, the image analysis means for protein maps comparison and the mass spectrometry (MALDI-TOF, MALDI-ESI) and bioinformatics means (sequence databases) for protein identification. For the protein interaction studies the yeast two-hybrid system is mostly employed. New concepts of disease diagnosis and treatment as well as new drugs design can be envisioned from the proteomic analysis.

Genomics↗
PubMed2026

ProtPen Combines Sequence- and Structure-based Approaches to Facilitate Protein Function Predictions on a Proteome-wide Scale.

Proteins of unknown function represent a significant gap in our understanding of biological processes, encompassing large portions of the proteomes of many organisms, especially prokaryotes. Addressing this gap is critical to understanding the biology and pathogenicity of such organisms. We introduce ProtPen, an open-source pipeline that facilitates protein function prediction by combining eggNOG-mapper for sequence-based annotation with Foldseek for rapid structural similarity searches using AlphaFold-predicted protein structures. Annotation results from both tools are merged and enriched with UniProt metadata to produce a comprehensive output suitable for downstream analysis. The pipeline requires only a FASTA input file with UniProt identifiers, and is designed to analyze data sets on the scale of whole proteomes. Benchmarking on a curated data set of well-characterized Pseudomonas aeruginosa proteins demonstrated an annotation accuracy of >90%, and highlighted the complementarity of sequence- and structure-based methods. Further evaluation of ProtPen included its application to biologically relevant data sets, comprising proteins of unknown function that exhibited significant differential abundances in a proteomics data set of P. aeruginosa, and uncharacterized glycoproteins from Haloferax volcanii. ProtPen is readily extensible to incorporate additional protein function prediction tools. In summary, this pipeline facilitates the systemwide annotation of proteins of unknown function from proteomic data sets and whole proteomes.

Pseudomonas aeruginosa↗
PubMed2025

Comprehensive discovery and functional characterization of the noncanonical proteome.

The systematic identification and functional characterization of noncanonical translation products, such as novel peptides, will facilitate the understanding of the human genome and provide new insights into cell biology. Here, we constructed a high-coverage peptide sequencing reference library with 11,668,944 open reading frames and employed an ultrafiltration tandem mass spectrometry assay to identify novel peptides. Through these methods, we discovered 8945 previously unannotated peptides from normal gastric tissues, gastric cancer tissues and cell lines, nearly half of which were derived from noncoding RNAs. Moreover, our CRISPR screening revealed that 1161 peptides are involved in tumor cell proliferation. The presence and physiological function of a subset of these peptides, selected based on screening scores, amino acid length, and various indicators, were verified through Flag-knockin and multiple other methods. To further characterize the potential regulatory mechanisms involved, we constructed a framework based on artificial intelligence structure prediction and peptide‒protein interaction network analysis for the top 100 candidates and revealed that these cancer-related peptides have diverse subcellular locations and participate in organelle-specific processes. Further investigation verified the interacting partners of pep1-nc-OLMALINC, pep5-nc-TRHDE-AS1, pep-nc-ZNF436-AS1 and pep2-nc-AC027045.3, and the functions of these peptides in mitochondrial complex assembly, energy metabolism, and cholesterol metabolism, respectively. We showed that pep5-nc-TRHDE-AS1 and pep2-nc-AC027045.3 had substantial impacts on tumor growth in xenograft models. Furthermore, the dysregulation of these four peptides is closely correlated with clinical prognosis. Taken together, our study provides a comprehensive characterization of the noncanonical proteome, and highlights critical roles of these previously unannotated peptides in cancer biology.

Humans↗
PubMed2005

Whole-proteome prediction of protein function via graph-theoretic analysis of interaction maps.

MOTIVATION: Determining protein function is one of the most important problems in the post-genomic era. For the typical proteome, there are no functional annotations for one-third or more of its proteins. Recent high-throughput experiments have determined proteome-scale protein physical interaction maps for several organisms. These physical interactions are complemented by an abundance of data about other types of functional relationships between proteins, including genetic interactions, knowledge about co-expression and shared evolutionary history. Taken together, these pairwise linkages can be used to build whole-proteome protein interaction maps. RESULTS: We develop a network-flow based algorithm, FunctionalFlow, that exploits the underlying structure of protein interaction maps in order to predict protein function. In cross-validation testing on the yeast proteome, we show that FunctionalFlow has improved performance over previous methods in predicting the function of proteins with few (or no) annotated protein neighbors. By comparing several methods that use protein interaction maps to predict protein function, we demonstrate that FunctionalFlow performs well because it takes advantage of both network topology and some measure of locality. Finally, we show that performance can be improved substantially as we consider multiple data sources and use them to create weighted interaction networks. AVAILABILITY: http://compbio.cs.princeton.edu/function

Algorithms↗
PubMed2006

Tissue heterogeneity of the mammalian mitochondrial proteome.

The functionality of the mitochondrion is primarily determined by nuclear encoded proteins. The mitochondrial functional requirements of different tissues vary from a significant biosynthetic role (liver) to a primarily energy metabolism-oriented organelle (heart). The purpose of this study was to compare the mitochondrial proteome from four different tissues of the rat, brain, liver, heart, and kidney, to provide insight into the extent of mitochondrial heterogeneity and to further characterize the overall mitochondrial proteome. Mitochondria were isolated, solubilized, digested, and subjected to quantitative liquid chromatography-mass spectroscopy. Of the 16,950 distinct peptides detected, 8,045 proteins were identified. High-confidence identification threshold was reached by 1,162 peptides, which were further analyzed. Of these 1,162 proteins, 1,149 were significantly different in content (P and q values < 0.05) between at least 2 tissues, whereas 13 were not significantly different between any tissues. Confirmation of the mitochondrial origin of proteins was determined from the literature or via NH(2)-terminal mitochondrial localization signals. With these criteria, 382 proteins in the significantly different groups were confirmed to be mitochondrial, and 493 could not be confirmed to be mitochondrial but were not definitively localized elsewhere in the cell. A total of 145 proteins were assigned to the rat mitochondrial proteome for the first time via their NH(2)-terminal mitochondrial localization signals. Among the proteins that were not significantly different between tissues, three were confirmed to be mitochondrial. Most notable of the significantly different proteins were histone family proteins and several structural proteins, including tubulin and intermediate filaments. The mitochondrial proteome from each tissue had very specific characteristics indicative of different functional emphasis. These data confirm the notion that mitochondria are tuned by the nucleus for specific functions in different tissues.

Amino Acid Sequence↗
PubMed2026

Role of semaphorin 4f in cardiac fibroblasts to regulate matrix production through actin remodeling and YAP/TAZ activation.

Cardiac fibrosis remains a critical determinant of adverse outcomes in heart disease, yet effective anti-fibrotic therapies are lacking. While multiple semaphorin family members participate in cardiovascular pathophysiology, the role of semaphorin 4f (Sema4f) in cardiac fibrosis remains unexplored. This study investigates the role and mechanisms of Sema4f in fibrotic remodeling post-myocardial infarction (MI). We employed flow cytometry to characterize cell type-specific Sema4f expression patterns in post-MI hearts. Lineage-specific knockout mice (fibroblast vs. myeloid) were subjected to left anterior descending ligation to assess functional consequences. Proteomic analysis of Sema4f-deficient cardiac fibroblasts was conducted to identify downstream effectors. Key pathways were subsequently validated using pharmacological inhibitors. We found that Sema4f expression was markedly upregulated during the fibrotic phase post-MI, primarily due to fibroblast activation. Fibroblast-, but not myeloid-, specific Sema4f deletion significantly reduced fibrosis and improved cardiac function. Proteomic profiling revealed that Sema4f deficiency led to downregulation of pro-fibrotic gene expression, which was associated with impaired actin cytoskeletal remodeling and decreased nuclear translocation of YAP/TAZ. Pharmacological inhibition of either actin remodeling or YAP/TAZ activity attenuated fibrosis, whereas YAP/TAZ activation abolished the anti-fibrotic effects of Sema4f knockout. Our study provides the first evidence demonstrating the functional role of Sema4f in cardiac fibroblast activation and fibrosis progression. We have identified a fibroblast-specific mechanism mediated by the Sema4f-actin cytoskeleton-YAP/TAZ axis, offering novel mechanistic insights into fibrosis regulation and revealing a promising therapeutic target for cardiac fibrosis with potential clinical applications.

Animals↗
PubMed2006

Comparative proteomic analysis reveals a function of the novel death receptor-associated protein BRE in the regulation of prohibitin and p53 expression and proliferation.

The brain and reproductive organ expressed (BRE) gene encodes a highly conserved stress-modulating protein. To gain further insight into the function of this gene, we used comparative proteomics to investigate the protein profiles of C2C12 and D122 cells resulting from small interfering RNA (siRNA)-mediated silencing as well as overexpression of BRE. Silencing of BRE in C2C12 cells, using siRNA, resulted in up-regulated Akt-3 and carbonic anhydrase III expression, while the 26S proteasome regulatory subunit S14 and prohibitin were down-regulated. Prohibitin is a potential tumour suppressor gene, which can directly interact with p53. We found that cell proliferation was significantly increased after knockdown of BRE, concomitant with reduced p53 and prohibitin expression. In contrast, we observed decreased proliferation and up-regulation of p53 and prohibitin when BRE was overexpressed in the D122 cell line. In total, five proteins were found to be up-regulated after BRE over-expression. The majority of these proteins can target or crosstalk with NF-kappaB, which plays a central role in regulating cell proliferation, differentiation and survival. Our results establish a crucial role for BRE in the regulation of key proteins of the cellular stress-response machinery and provide an explanation for the multifunctional nature of BRE.

Animals↗
PubMed2002

Quantitative proteomic analysis of Myc oncoprotein function.

This study applies a new quantitative proteomics technology to the analysis of the function of the Myc oncoprotein in mammalian cells. Employing isotope-coded affinity tag (ICAT) reagent labeling and tandem mass spectrometry, the global pattern of protein expression in rat myc-null cells was compared with that of myc-plus cells (myc-null cells in which myc has been introduced) to generate a differential protein expression catalog. Expression differences among many functionally related proteins were identified, including reduction of proteases, induction of protein synthesis pathways and upregulation of anabolic enzymes in myc-plus cells, which are predicted to lead to increased cell mass (cell growth). In addition, reduction in the levels of adhesion molecules, actin network proteins and Rho pathway proteins were observed in myc-plus cells, leading to reduced focal adhesions and actin stress fibers as well as altered morphology. These effects are dependent on the highly conserved Myc Box II region. Our results reveal a novel cytoskeletal function for Myc and indicate the feasibility of quantitative whole-proteome analysis in mammalian cells.

Animals↗
PubMed2002

Functional organization of the yeast proteome by systematic analysis of protein complexes.

Most cellular processes are carried out by multiprotein complexes. The identification and analysis of their components provides insight into how the ensemble of expressed proteins (proteome) is organized into functional units. We used tandem-affinity purification (TAP) and mass spectrometry in a large-scale approach to characterize multiprotein complexes in Saccharomyces cerevisiae. We processed 1,739 genes, including 1,143 human orthologues of relevance to human biology, and purified 589 protein assemblies. Bioinformatic analysis of these assemblies defined 232 distinct multiprotein complexes and proposed new cellular roles for 344 proteins, including 231 proteins with no previous functional annotation. Comparison of yeast and human complexes showed that conservation across species extends from single proteins to their molecular environment. Our analysis provides an outline of the eukaryotic proteome as a network of protein complexes at a level of organization beyond binary interactions. This higher-order map contains fundamental biological information and offers the context for a more reasoned and informed approach to drug discovery.

Cells, Cultured↗
PubMed2005

Understanding protein trafficking in plant cells through proteomics.

The functions of approximately one-third of the proteins encoded by the Arabidopsis thaliana genome are completely unknown. Moreover, many annotations of the remainder of the genome supply tentative functions, at best. Knowing the ultimate localization of these proteins, as well as the pathways used for getting there, may provide clues as to their functions. The putative localization of most proteins currently relies on in silico-based bioinformatics approaches, which, unfortunately, often result in erroneous predictions. Emerging proteomics techniques coupled with other systems biology approaches now provide researchers with a plethora of methods for elucidating the final location of these proteins on a large scale, as well as the ability to dissect protein-sorting pathways in plants.

Databases, Protein↗
PubMed2002

Functional materials for microscale genomic and proteomic analyses.

The design of functional materials for genomic and proteomic analyses in microscale systems has begun to mature, from materials designed for capillary-based electrophoresis systems to those tailored for microfluidic-based or 'chip-based' platforms. In particular, recent research has focused on evaluating different polymer chemistries for microchannel surface passivation and improved DNA separation matrix performance. Additionally, novel bioconjugate materials designed specifically for electrophoretic separations in microscale channels are facilitating new separation modalities.

Acrylamides↗
PubMed2003

A proteomics strategy to elucidate functional protein-protein interactions applied to EGF signaling.

Mass spectrometry-based proteomics can reveal protein-protein interactions on a large scale, but it has been difficult to separate background binding from functionally important interactions and still preserve weak binders. To investigate the epidermal growth factor receptor (EGFR) pathway, we employ stable isotopic amino acids in cell culture (SILAC) to differentially label proteins in EGF-stimulated versus unstimulated cells. Combined cell lysates were affinity-purified over the SH2 domain of the adapter protein Grb2 (GST-SH2 fusion protein) that specifically binds phosphorylated EGFR and Src homologous and collagen (Shc) protein. We identified 228 proteins, of which 28 were selectively enriched upon stimulation. EGFR and Shc, which interact directly with the bait, had large differential ratios. Many signaling molecules specifically formed complexes with the activated EGFR-Shc, as did plectin, epiplakin, cytokeratin networks, histone H3, the glycosylphosphatidylinositol (GPI)-anchored molecule CD59, and two novel proteins. SILAC combined with modification-based affinity purification is a useful approach to detect specific and functional protein-protein interactions.

Epidermal Growth Factor↗
PubMed2003

Structural proteomics: toward high-throughput structural biology as a tool in functional genomics.

Structural proteomics is the determination of atomic resolution three-dimensional protein structures on a genome-wide scale in order to better understand the relationship between protein sequence, structure, and function. Here we describe our ongoing structural proteomics project on the nonmembrane proteins of the archeaon, Methanobacterium thermoautotrophicum. This article provides a snapshot of an ongoing pilot project in an emerging area of multidisciplinary research that involves bioinformatics, molecular biology, biochemistry, and instrumental methods such as NMR spectroscopy and X-ray crystallography. An assessment of the technical challenges in this type of large-scale project along with a comparison of the efficiency of sample production for both X-ray crystallography and NMR spectroscopy will be discussed. Examples of new insights into protein function and the relationship between structure and sequence will also be presented.

Bacterial Proteins↗
PubMed2004

Structure-based functional discovery of proteins: structural proteomics.

The discovery of biochemical and cellular functions of unannotated gene products begins with a database search of proteins with structure/sequence homologues based on known genes. Very recently, a number of frontier groups in structural biology proposed a new paradigm to predict biological functions of an unknown protein on the basis of its three-dimensional structure on a genomic scale. Structural proteomics (genomics), a research area for structure-based functional discovery, aims to complete the protein-folding universe of all gene products in a cell. It would lead us to a complete understanding of a living organism from protein structure. Two major complementary experimental techniques, X-ray crystallography and NMR spectroscopy, combined with recently developed high throughput methods have played a central role in structural proteomics research; however, an integration of these methodologies together with comparative modeling and electron microscopy would speed up the goal for completing a full dictionary of protein folding space in the near future.

Animals↗
PubMed2006

FCP: functional coverage of the proteome by structures.

MOTIVATION: Tools and resources for translating the remarkable growth witnessed in recent years in the number of protein structures determined experimentally into actual gain in the functional coverage of the proteome are becoming increasingly necessary. We introduce FCP, a publicly accessible web tool dedicated to analyzing the current state and trends of the population of structures within protein families. FCP offers both graphical and quantitative data on the degree of functional coverage of enzymes and nuclear receptors by existing structures, as well as on the bias observed in the distribution of structures along their respective functional classification schemes. AVAILABILITY: http://cgl.imim.es/fcp CONTACT: jmestres@imim.es.

Algorithms↗
PubMed2005

Rice proteome database: a step toward functional analysis of the rice genome.

The technique of proteome analysis using two-dimensional polyacrylamide gel electrophoresis (2D-PAGE) has the power to monitor global changes that occur in the protein complement of tissues and subcellular compartments. In this study, the proteins of rice were cataloged, a rice proteome database was constructed, and a functional characterization of some of the identified proteins was undertaken. Proteins extracted from various tissues and subcellular compartments in rice were separated by 2D-PAGE and an image analyzer was used to construct a display of the proteins. The Rice Proteome Database contains 23 reference maps based on 2D-PAGE of proteins from various rice tissues and subcellular compartments. These reference maps comprise 13129 identified proteins, and the amino acid sequences of 5092 proteins are entered in the database. Major proteins involved in growth or stress responses were identified using the proteome approach. Some of these proteins, including a beta-tubulin, calreticulin, and ribulose-1,5-bisphosphate carboxylase/oxygenase activase in rice, have unexpected functions. The information obtained from the Rice Proteome Database will aid in cloning the genes for and predicting the function of unknown proteins.

Calreticulin↗
PubMed2005

Rice proteome analysis: a step toward functional analysis of the rice genome.

The technique of proteome analysis using 2-DE has the power to monitor global changes that occur in the protein complement of tissues and subcellular compartments. In this review, we describe construction of the rice proteome database, the cataloging of rice proteins, and the functional characterization of some of the proteins identified. Initially, proteins extracted from various tissues and organelles were separated by 2-DE and an image analyzer was used to construct a display or reference map of the proteins. The rice proteome database currently contains 23 reference maps based on 2-DE of proteins from different rice tissues and subcellular compartments. These reference maps comprise 13 129 rice proteins, and the amino acid sequences of 5092 of these proteins are entered in the database. Major proteins involved in growth or stress responses have been identified by using a proteomics approach and some of these proteins have unique functions. Furthermore, initial work has also begun on analyzing the phosphoproteome and protein-protein interactions in rice. The information obtained from the rice proteome database will aid in the molecular cloning of rice genes and in predicting the function of unknown proteins.

Calreticulin↗