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PubMed2005

A human protein atlas for normal and cancer tissues based on antibody proteomics.

Antibody-based proteomics provides a powerful approach for the functional study of the human proteome involving the systematic generation of protein-specific affinity reagents. We used this strategy to construct a comprehensive, antibody-based protein atlas for expression and localization profiles in 48 normal human tissues and 20 different cancers. Here we report a new publicly available database containing, in the first version, approximately 400,000 high resolution images corresponding to more than 700 antibodies toward human proteins. Each image has been annotated by a certified pathologist to provide a knowledge base for functional studies and to allow queries about protein profiles in normal and disease tissues. Our results suggest it should be possible to extend this analysis to the majority of all human proteins thus providing a valuable tool for medical and biological research.

Antibodies↗
PubMed2002

Gene expression profiling of prolonged cold ischemia and reperfusion in murine heart transplants.

BACKGROUND: Heart transplantation causes complex changes in the biological homeostasis of the graft. Current knowledge is restricted to a few genes and regulation of certain factors involved in ischemia-reperfusion (I/R) injury. Efficient strategies to prevent I/R injury, however, require a better understanding of its mechanisms. Using cDNA microarrays, we investigated gene expression profiles of murine cardiac isografts. METHODS: For microarray hybridization experiments, chips with 8,734 individual target sequences were used. Messenger RNA was extracted from hearts subjected to warm ischemia and different time periods of reperfusion or to prolonged cold ischemia or warm ischemia and transplantation. Native hearts served as controls. RESULTS: A set of 68 sequences was regulated in all hearts. In addition, grafts without cold ischemia showed differential expression of 65 sequences, which were not found in hearts transplanted after cold storage, and which in turn had 38 sequences regulated and not detected in grafts without cold ischemia. Overall, approximately 50% of regulated transcripts are expressed sequence tags (ESTs) with unknown function. Annotated genes encoded immune modulators (20% of sequences), receptor proteins, structural proteins, and proteins involved in metabolism. CONCLUSION: Our data demonstrate expression profiles of hearts subjected to prolonged cold ischemia or transplantation in an isogeneic setting. We have defined functional complexes and detected a substantial amount of ESTs encoding novel proteins. These studies may provide a molecular basis for further functional experiments and may help identify potential targets for modulation of postischemic inflammation.

Animals↗
PubMed2003

Recognizing complex, asymmetric functional sites in protein structures using a Bayesian scoring function.

The increase in known three-dimensional protein structures enables us to build statistical profiles of important functional sites in protein molecules. These profiles can then be used to recognize sites in large-scale automated annotations of new protein structures. We report an improved FEATURE system which recognizes functional sites in protein structures. FEATURE defines multi-level physico-chemical properties and recognizes sites based on the spatial distribution of these properties in the sites' microenvironments. It uses a Bayesian scoring function to compare a query region with the statistical profile built from known examples of sites and control nonsites. We have previously shown that FEATURE can accurately recognize calcium-binding sites and have reported interesting results scanning for calcium-binding sites in the entire Protein Data Bank. Here we report the ability of the improved FEATURE to characterize and recognize geometrically complex and asymmetric sites such as ATP-binding sites and disulfide bond-forming sites. FEATURE does not rely on conserved residues or conserved residue geometry of the sites. We also demonstrate that, in the absence of a statistical profile of the sites, FEATURE can use an artificially constructed profile based on a priori knowledge to recognize the sites in new structures, using redoxin active sites as an example.

Adenosine Triphosphate↗
PubMed1995

Novel protein families in archaean genomes.

In a quest for novel functions in archaea, all archaean hypothetical open reading frames (ORFs), as annotated in the Swiss-Prot protein sequence database, were used to search the latest databases for the identification of characterized homologues. Of the 95 hypothetical archaean ORFs, 25 were found to be homologous to another hypothetical archaean ORF, while 36 were homologous to non-archaean proteins, of which as many as 30 were homologous to a characterized protein family. Thus the level of sequence similarity in this set reaches 64%, while the level of function assignment is only 32%. Of the ORFs with predicted functions, 12 homologies are reported here for the first time and represent nine new functions and one gene duplication at an acetyl-coA synthetase locus. The novel functions include components of the transcriptional and translational apparatus, such as ribosomal proteins, modification enzymes and a translation initiation factor. In addition, new enzymes are identified in archaea, such as cobyric acid synthase, dCTP deaminase and the first archaean homologues of a new subclass of ATP binding proteins found in fungi. Finally, it is shown that the putative laminin receptor family of eukaryotes and an archaean homologue belong to the previously characterized ribosomal protein family S2 from eubacteria. From the present and previous work, the major implication is that archaea seem to have a mode of expression of genetic information rather similar to eukaryotes, while eubacteria may have proceeded into unique ways of transcription and translation. In addition, with the detection of proteins in various metabolic and genetic processes in archaea, we can further predict the presence of additional proteins involved in these processes.

Animal Population Groups↗
PubMed2006

Anopheles gambiae genome reannotation through synthesis of ab initio and comparative gene prediction algorithms.

BACKGROUND: Complete genome annotation is a necessary tool as Anopheles gambiae researchers probe the biology of this potent malaria vector. RESULTS: We reannotate the A. gambiae genome by synthesizing comparative and ab initio sets of predicted coding sequences (CDSs) into a single set using an exon-gene-union algorithm followed by an open-reading-frame-selection algorithm. The reannotation predicts 20,970 CDSs supported by at least two lines of evidence, and it lowers the proportion of CDSs lacking start and/or stop codons to only approximately 4%. The reannotated CDS set includes a set of 4,681 novel CDSs not represented in the Ensembl annotation but with EST support, and another set of 4,031 Ensembl-supported genes that undergo major structural and, therefore, probably functional changes in the reannotated set. The quality and accuracy of the reannotation was assessed by comparison with end sequences from 20,249 full-length cDNA clones, and evaluation of mass spectrometry peptide hit rates from an A. gambiae shotgun proteomic dataset confirms that the reannotated CDSs offer a high quality protein database for proteomics. We provide a functional proteomics annotation, ReAnoXcel, obtained by analysis of the new CDSs through the AnoXcel pipeline, which allows functional comparisons of the CDS sets within the same bioinformatic platform. CDS data are available for download. CONCLUSION: Comprehensive A. gambiae genome reannotation is achieved through a combination of comparative and ab initio gene prediction algorithms.

Algorithms↗
PubMed2006

Intermediary metabolism in sea urchin: the first inferences from the genome sequence.

The genome sequence of the purple sea urchin Strongylocentrotus purpuratus recently became available. We report the results of functional annotation and initial analysis of more than 2300 proteins predicted to be involved in metabolite transport and enzymatic conversion in sea urchin. The comparison of various reconstructed biosynthetic and catabolic pathways in sea urchin to those known in other genomes suggests the overall similarity of the sea urchin metabolism to that of the vertebrates, with relatively small but non-trivial differences from both vertebrates and protostomes. There are several examples of two parallel, non-orthologous solutions for the same molecular function in sea urchin, in contrast with the other completely sequenced metazoans that tend to contain just one version of the same function. There are also genes that appear to be close phylogenetic neighbors of plant or bacterial homologs, as opposed to homologs in other Metazoa. The evolutionary and functional significance of these variations is discussed.

Amino Acids↗
PubMed2005

Global profiling of Shewanella oneidensis MR-1: expression of hypothetical genes and improved functional annotations.

The gamma-proteobacterium Shewanella oneidensis strain MR-1 is a metabolically versatile organism that can reduce a wide range of organic compounds, metal ions, and radionuclides. Similar to most other sequenced organisms, approximately 40% of the predicted ORFs in the S. oneidensis genome were annotated as uncharacterized "hypothetical" genes. We implemented an integrative approach by using experimental and computational analyses to provide more detailed insight into gene function. Global expression profiles were determined for cells after UV irradiation and under aerobic and suboxic growth conditions. Transcriptomic and proteomic analyses confidently identified 538 hypothetical genes as expressed in S. oneidensis cells both as mRNAs and proteins (33% of all predicted hypothetical proteins). Publicly available analysis tools and databases and the expression data were applied to improve the annotation of these genes. The annotation results were scored by using a seven-category schema that ranked both confidence and precision of the functional assignment. We were able to identify homologs for nearly all of these hypothetical proteins (97%), but could confidently assign exact biochemical functions for only 16 proteins (category 1; 3%). Altogether, computational and experimental evidence provided functional assignments or insights for 240 more genes (categories 2-5; 45%). These functional annotations advance our understanding of genes involved in vital cellular processes, including energy conversion, ion transport, secondary metabolism, and signal transduction. We propose that this integrative approach offers a valuable means to undertake the enormous challenge of characterizing the rapidly growing number of hypothetical proteins with each newly sequenced genome.

Gene Expression Profiling↗
PubMed2005

LS-SNP: large-scale annotation of coding non-synonymous SNPs based on multiple information sources.

MOTIVATION: The NCBI dbSNP database lists over 9 million single nucleotide polymorphisms (SNPs) in the human genome, but currently contains limited annotation information. SNPs that result in amino acid residue changes (nsSNPs) are of critical importance in variation between individuals, including disease and drug sensitivity. RESULTS: We have developed LS-SNP, a genomic scale software pipeline to annotate nsSNPs. LS-SNP comprehensively maps nsSNPs onto protein sequences, functional pathways and comparative protein structure models, and predicts positions where nsSNPs destabilize proteins, interfere with the formation of domain-domain interfaces, have an effect on protein-ligand binding or severely impact human health. It currently annotates 28,043 validated SNPs that produce amino acid residue substitutions in human proteins from the SwissProt/TrEMBL database. Annotations can be viewed via a web interface either in the context of a genomic region or by selecting sets of SNPs, genes, proteins or pathways. These results are useful for identifying candidate functional SNPs within a gene, haplotype or pathway and in probing molecular mechanisms responsible for functional impacts of nsSNPs. AVAILABILITY: http://www.salilab.org/LS-SNP CONTACT: rachelk@salilab.org SUPPLEMENTARY INFORMATION: http://salilab.org/LS-SNP/supp-info.pdf.

Algorithms↗
PubMed2001

Genomewide function conservation and phylogeny in the Herpesviridae.

The Herpesviridae are a large group of well-characterized double-stranded DNA viruses for which many complete genome sequences have been determined. We have extracted protein sequences from all predicted open reading frames of 19 herpesvirus genomes. Sequence comparison and protein sequence clustering methods have been used to construct herpesvirus protein homologous families. This resulted in 1692 proteins being clustered into 243 multiprotein families and 196 singleton proteins. Predicted functions were assigned to each homologous family based on genome annotation and published data and each family classified into seven broad functional groups. Phylogenetic profiles were constructed for each herpesvirus from the homologous protein families and used to determine conserved functions and genomewide phylogenetic trees. These trees agreed with molecular-sequence-derived trees and allowed greater insight into the phylogeny of ungulate and murine gammaherpesviruses.

Animals↗
PubMed2006

Isoflurane modulates genomic expression in rat amygdala.

General anesthesia, at a minimum, provides amnesia and unresponsiveness. Although anesthetics have many modulatory effects on neuronal ionophore protein complexes, it is not clear that the resulting electrophysiologic changes are the sole mechanisms of clinical anesthetic action. Cells respond to environmental changes in several ways, including alterations in DNA transcription leading to changes in the cell's proteins. We sought to expose the changes in global genomic expression, seeking potential targets involved in the processes of anesthetic-induced amnesia, and persistent long-term side effects of general anesthesia, including nausea and postoperative cognitive decline. Using Affymetrix GeneChips, we surveyed changes in expression across the entire expressed genome of Sprague-Dawley rat (n = 10 baseline, n = 6 isoflurane) basolateral amygdala 6 h after exposure to 15 min of 2% (1.4 MAC) isoflurane. Isoflurane administration was associated with altered expression in 269 unique genes possessing functional annotation. Affected genes were related to DNA transcription, protein synthesis, metabolism, signaling cascades, cytoskeletal structural proteins, and neural-specific proteins, among others. Even brief exposure to isoflurane leads to widespread changes in the genetic control in the amygdala 6 h after exposure. Gene expression is a dynamic process that may explain some long-term effects of anesthesia and that has the potential to modulate some of those effects using specific molecular therapeutics.

Amygdala↗
PubMed2006

Prediction of yeast protein-protein interaction network: insights from the Gene Ontology and annotations.

A map of protein-protein interactions provides valuable insight into the cellular function and machinery of a proteome. By measuring the similarity between two Gene Ontology (GO) terms with a relative specificity semantic relation, here, we proposed a new method of reconstructing a yeast protein-protein interaction map that is solely based on the GO annotations. The method was validated using high-quality interaction datasets for its effectiveness. Based on a Z-score analysis, a positive dataset and a negative dataset for protein-protein interactions were derived. Moreover, a gold standard positive (GSP) dataset with the highest level of confidence that covered 78% of the high-quality interaction dataset and a gold standard negative (GSN) dataset with the lowest level of confidence were derived. In addition, we assessed four high-throughput experimental interaction datasets using the positives and the negatives as well as GSPs and GSNs. Our predicted network reconstructed from GSPs consists of 40,753 interactions among 2259 proteins, and forms 16 connected components. We mapped all of the MIPS complexes except for homodimers onto the predicted network. As a result, approximately 35% of complexes were identified interconnected. For seven complexes, we also identified some nonmember proteins that may be functionally related to the complexes concerned. This analysis is expected to provide a new approach for predicting the protein-protein interaction maps from other completely sequenced genomes with high-quality GO-based annotations.

Databases, Genetic↗
PubMed2002

Applications of InterPro in protein annotation and genome analysis.

The applications of InterPro span a range of biologically important areas that includes automatic annotation of protein sequences and genome analysis. In automatic annotation of protein sequences InterPro has been utilised to provide reliable characterisation of sequences, identifying them as candidates for functional annotation. Rules based on the InterPro characterisation are stored and operated through a database called RuleBase. RuleBase is used as the main tool in the sequence database group at the EBI to apply automatic annotation to unknown sequences. The annotated sequences are stored and distributed in the TrEMBL protein sequence database. InterPro also provides a means to carry out statistical and comparative analyses of whole genomes. In the Proteome Analysis Database, InterPro analyses have been combined with other analyses based on CluSTr, the Gene Ontology (GO) and structural information on the proteins.

Amino Acid Sequence↗
PubMed2005

Protein expression, crystallization and preliminary X-ray crystallographic studies of YjbK from Bacillus subtilis.

B. subtilis YjbK is a protein with 190 residues of uncharacterized function, it has been annotated by Pfam database as a member of adenylate cyclase family (EC: 4.6.1.1). In order to identify its exact function via structural studies, yjbK gene was amplified from B. subtilis genomic DNA and cloned into expression vector pET21-DEST. The protein was expressed in a soluble form in E. coli and purified to homogeneity. YjbK was crystallized and diffracted to a resolution of 2.0 A in-house. The crystals belong to P1 space group, with unit cell parameters a = 32.38 A, b = 34.69 A, c = 46.02 A, alpha = 96.560 degrees, beta = 99.683 degrees, gamma = 111.333 degrees. There is one molecule per asymmetric unit.

Amino Acid Sequence↗
PubMed2006

Intrinsic disorder is a common feature of hub proteins from four eukaryotic interactomes.

Recent proteome-wide screening approaches have provided a wealth of information about interacting proteins in various organisms. To test for a potential association between protein connectivity and the amount of predicted structural disorder, the disorder propensities of proteins with various numbers of interacting partners from four eukaryotic organisms (Caenorhabditis elegans, Saccharomyces cerevisiae, Drosophila melanogaster, and Homo sapiens) were investigated. The results of PONDR VL-XT disorder analysis show that for all four studied organisms, hub proteins, defined here as those that interact with > or = 10 partners, are significantly more disordered than end proteins, defined here as those that interact with just one partner. The proportion of predicted disordered residues, the average disorder score, and the number of predicted disordered regions of various lengths were higher overall in hubs than in ends. A binary classification of hubs and ends into ordered and disordered subclasses using the consensus prediction method showed a significant enrichment of wholly disordered proteins and a significant depletion of wholly ordered proteins in hubs relative to ends in worm, fly, and human. The functional annotation of yeast hubs and ends using GO categories and the correlation of these annotations with disorder predictions demonstrate that proteins with regulation, transcription, and development annotations are enriched in disorder, whereas proteins with catalytic activity, transport, and membrane localization annotations are depleted in disorder. The results of this study demonstrate that intrinsic structural disorder is a distinctive and common characteristic of eukaryotic hub proteins, and that disorder may serve as a determinant of protein interactivity.

Amino Acids↗
PubMed2000

Towards understanding the first genome sequence of a crenarchaeon by genome annotation using clusters of orthologous groups of proteins (COGs).

BACKGROUND: Standard archival sequence databases have not been designed as tools for genome annotation and are far from being optimal for this purpose. We used the database of Clusters of Orthologous Groups of proteins (COGs) to reannotate the genomes of two archaea, Aeropyrum pernix, the first member of the Crenarchaea to be sequenced, and Pyrococcus abyssi. RESULTS: A. pernix and P. abyssi proteins were assigned to COGs using the COGNITOR program; the results were verified on a case-by-case basis and augmented by additional database searches using the PSI-BLAST and TBLASTN programs. Functions were predicted for over 300 proteins from A. pernix, which could not be assigned a function using conventional methods with a conservative sequence similarity threshold, an approximately 50% increase compared to the original annotation. A. pernix shares most of the conserved core of proteins that were previously identified in the Euryarchaeota. Cluster analysis or distance matrix tree construction based on the co-occurrence of genomes in COGs showed that A. pernix forms a distinct group within the archaea, although grouping with the two species of Pyrococci, indicative of similar repertoires of conserved genes, was observed. No indication of a specific relationship between Crenarchaeota and eukaryotes was obtained in these analyses. Several proteins that are conserved in Euryarchaeota and most bacteria are unexpectedly missing in A. pernix, including the entire set of de novo purine biosynthesis enzymes, the GTPase FtsZ (a key component of the bacterial and euryarchaeal cell-division machinery), and the tRNA-specific pseudouridine synthase, previously considered universal. A. pernix is represented in 48 COGs that do not contain any euryarchaeal members. Many of these proteins are TCA cycle and electron transport chain enzymes, reflecting the aerobic lifestyle of A. pernix. CONCLUSIONS: Special-purpose databases organized on the basis of phylogenetic analysis and carefully curated with respect to known and predicted protein functions provide for a significant improvement in genome annotation. A differential genome display approach helps in a systematic investigation of common and distinct features of gene repertoires and in some cases reveals unexpected connections that may be indicative of functional similarities between phylogenetically distant organisms and of lateral gene exchange.

Archaea↗
PubMed2003

Functional fingerprints of folds: evidence for correlated structure-function evolution.

Using structural similarity clustering of protein domains: protein domain universe graph (PDUG), and a hierarchical functional annotation: gene ontology (GO) as two evolutionary lenses, we find that each structural cluster (domain fold) exhibits a distribution of functions that is unique to it. These functional distributions are functional fingerprints that are specific to characteristic structural clusters and vary from cluster to cluster. Furthermore, as structural similarity threshold for domain clustering in the PDUG is relaxed we observe an influx of earlier-diverged domains into clusters. These domains join clusters without destroying the functional fingerprint. These results can be understood in light of a divergent evolution scenario that posits correlated divergence of structural and functional traits in protein domains from one or few progenitors.

Adenosine Triphosphate↗
PubMed2006

The proteomes of neurotransmitter receptor complexes form modular networks with distributed functionality underlying plasticity and behaviour.

Neuronal synapses play fundamental roles in information processing, behaviour and disease. Neurotransmitter receptor complexes, such as the mammalian N-methyl-D-aspartate receptor complex (NRC/MASC) comprising 186 proteins, are major components of the synapse proteome. Here we investigate the organisation and function of NRC/MASC using a systems biology approach. Systematic annotation showed that the complex contained proteins implicated in a wide range of cognitive processes, synaptic plasticity and psychiatric diseases. Protein domains were evolutionarily conserved from yeast, but enriched with signalling domains associated with the emergence of multicellularity. Mapping of protein-protein interactions to create a network representation of the complex revealed that simple principles underlie the functional organisation of both proteins and their clusters, with modularity reflecting functional specialisation. The known functional roles of NRC/MASC proteins suggest the complex co-ordinates signalling to diverse effector pathways underlying neuronal plasticity. Importantly, using quantitative data from synaptic plasticity experiments, our model correctly predicts robustness to mutations and drug interference. These studies of synapse proteome organisation suggest that molecular networks with simple design principles underpin synaptic signalling properties with important roles in physiology, behaviour and disease.

Animals↗
PubMed2005

ProRule: a new database containing functional and structural information on PROSITE profiles.

MOTIVATION: Increase the discriminatory power of PROSITE profiles to facilitate function determination and provide biologically relevant information about domains detected by profiles for the annotation of proteins. SUMMARY: We have created a new database, ProRule, which contains additional information about PROSITE profiles. ProRule contains notably the position of structurally and/or functionally critical amino acids, as well as the condition they must fulfill to play their biological role. These supplementary data should help function determination and annotation of the UniProt Swiss-Prot knowledgebase. ProRule also contains information about the domain detected by the profile in the Swiss-Prot line format. Hence, ProRule can be used to make Swiss-Prot annotation more homogeneous and consistent. The format of ProRule can be extended to provide information about combination of domains. AVAILABILITY: ProRule can be accessed through ScanProsite at http://www.expasy.org/tools/scanprosite. A file containing the rules will be made available under the PROSITE copyright conditions on our ftp site (ftp://www.expasy.org/databases/prosite/) by the next PROSITE release.

Amino Acid Sequence↗