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Results for “Protein function”

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PubMed2003

Functionality of system components: conservation of protein function in protein feature space.

Many protein features useful for prediction of protein function can be predicted from sequence, including posttranslational modifications, subcellular localization, and physical/chemical properties. We show here that such protein features are more conserved among orthologs than paralogs, indicating they are crucial for protein function and thus subject to selective pressure. This means that a function prediction method based on sequence-derived features may be able to discriminate between proteins with different function even when they have highly similar structure. Also, such a method is likely to perform well on organisms other than the one on which it was trained. We evaluate the performance of such a method, ProtFun, which relies on protein features as its sole input, and show that the method gives similar performance for most eukaryotes and performs much better than anticipated on archaea and bacteria. From this analysis, we conclude that for the posttranslational modifications studied, both the cellular use and the sequence motifs are conserved within Eukarya.

Amino Acid Sequence↗

PubMed2003

Vaccinia complement control protein: multi-functional protein and a potential wonder drug.

Vaccinia virus complement control protein (VCP) was one of the first viral molecules demonstrated to have a role in blocking complement and hence in the evasion of host defense. Structurally it is very similar to the human C4b-BP and the other members of complement control protein. Functionally it is most similar to the CR1 protein. VCP blocks both major pathways of complement activation. The crystal structure of VCP was determined a little over a year ago and it is the only known structure of an intact and complete complement control protein. In addition to binding complement, VCP also binds to heparin. These two binding abilities can take place simultaneously and contribute to its many function and to its potential use in several inflammatory diseases, e.g. Alzheimer's disease (AD), CNS injury, xenotransplantation, etc. making it a truly fascinating molecule and potential drug.

Complement Activation↗

PubMed2001

Automated structure-based prediction of functional sites in proteins: applications to assessing the validity of inheriting protein function from homology in genome annotation and to protein docking.

A major problem in genome annotation is whether it is valid to transfer the function from a characterised protein to a homologue of unknown activity. Here, we show that one can employ a strategy that uses a structure-based prediction of protein functional sites to assess the reliability of functional inheritance. We have automated and benchmarked a method based on the evolutionary trace approach. Using a multiple sequence alignment, we identified invariant polar residues, which were then mapped onto the protein structure. Spatial clusters of these invariant residues formed the predicted functional site. For 68 of 86 proteins examined, the method yielded information about the observed functional site. This algorithm for functional site prediction was then used to assess the validity of transferring the function between homologues. This procedure was tested on 18 pairs of homologous proteins with unrelated function and 70 pairs of proteins with related function, and was shown to be 94 % accurate. This automated method could be linked to schemes for genome annotation. Finally, we examined the use of functional site prediction in protein-protein and protein-DNA docking. The use of predicted functional sites was shown to filter putative docked complexes with a discrimination similar to that obtained by manually including biological information about active sites or DNA-binding residues.

Algorithms↗

PubMed2003

Global protein function prediction from protein-protein interaction networks.

Determining protein function is one of the most challenging problems of the post-genomic era. The availability of entire genome sequences and of high-throughput capabilities to determine gene coexpression patterns has shifted the research focus from the study of single proteins or small complexes to that of the entire proteome. In this context, the search for reliable methods for assigning protein function is of primary importance. There are various approaches available for deducing the function of proteins of unknown function using information derived from sequence similarity or clustering patterns of co-regulated genes, phylogenetic profiles, protein-protein interactions (refs. 5-8 and Samanta, M.P. and Liang, S., unpublished data), and protein complexes. Here we propose the assignment of proteins to functional classes on the basis of their network of physical interactions as determined by minimizing the number of protein interactions among different functional categories. Function assignment is proteome-wide and is determined by the global connectivity pattern of the protein network. The approach results in multiple functional assignments, a consequence of the existence of multiple equivalent solutions. We apply the method to analyze the yeast Saccharomyces cerevisiae protein-protein interaction network. The robustness of the approach is tested in a system containing a high percentage of unclassified proteins and also in cases of deletion and insertion of specific protein interactions.

Algorithms↗

PubMed2005

Improvement in protein functional site prediction by distinguishing structural and functional constraints on protein family evolution using computational design.

The prediction of functional sites in newly solved protein structures is a challenge for computational structural biology. Most methods for approaching this problem use evolutionary conservation as the primary indicator of the location of functional sites. However, sequence conservation reflects not only evolutionary selection at functional sites to maintain protein function, but also selection throughout the protein to maintain the stability of the folded state. To disentangle sequence conservation due to protein functional constraints from sequence conservation due to protein structural constraints, we use all atom computational protein design methodology to predict sequence profiles expected under solely structural constraints, and to compute the free energy difference between the naturally occurring amino acid and the lowest free energy amino acid at each position. We show that functional sites are more likely than non-functional sites to have computed sequence profiles which differ significantly from the naturally occurring sequence profiles and to have residues with sub-optimal free energies, and that incorporation of these two measures improves sequence based prediction of protein functional sites. The combined sequence and structure based functional site prediction method has been implemented in a publicly available web server.

Algorithms↗

PubMed1986

An abnormal plasma distribution of protein S occurs in functional protein S deficiency.

Protein S is a natural anticoagulant present in the plasma that serves as a cofactor for activated protein C. Patients deficient in protein S are subject to recurrent venous thrombotic disease. Protein S deficiency differs from other plasma protein deficiencies in that deficient patients often have normal or only mildly reduced levels of protein S in their plasma as detected by conventional immunologic methods but have markedly reduced functional protein S levels. This apparent discrepancy is due to the presence of two forms of protein S in plasma. The protein S is present free and in a complex with C4b-binding protein. The free form is functionally active, whereas the bound form is not. Examination by crossed immunoelectrophoresis of 31 functionally protein S-deficient individuals from seven families reveals that 29 of the 31 have all or most of their protein S complexed to C4b-binding protein with little or no free protein and have correspondingly low levels of protein S functional activity (type I deficiency). Two related protein S-deficient individuals show a different type of distribution with little or no protein S, either bound or free (type II deficiency). The detection and classification of protein S-deficient individuals requires the application of both a functional assay and an assessment of protein S distribution between bound and free forms.

Carrier Proteins↗

PubMed2004

Unveiling functional protein motions with picosecond x-ray crystallography and molecular dynamics simulations.

A joint analysis of all-atom molecular dynamics (MD) calculations and picosecond time-resolved x-ray structures was performed to gain single-molecule insights into mechanisms of protein function. Ensemble-averaged MD simulations of the L29F mutant of myoglobin after ligand dissociation reproduce the direction, amplitude, and time scales of crystallographically determined structural changes. This close agreement with experiments at comparable resolution in space and time validates the individual MD trajectories. From 1,700 single-molecule trajectories, we identified and structurally characterized a conformational switch that directs dissociated ligands to one of two nearby protein cavities. Subsequent ligand migration proceeds through a network of transiently interconnected internal cavities, with passage between them involving correlated protein-ligand motions. The simulations also suggest how picosecond protein motions modulate the functional dissociation of oxygen and suppress the geminate recombination of toxic carbon monoxide.

Carbon Monoxide↗

PubMed2006

Rank information: a structure-independent measure of evolutionary trace quality that improves identification of protein functional sites.

Protein functional sites are key targets for drug design and protein engineering, but their large-scale experimental characterization remains difficult. The evolutionary trace (ET) is a computational approach to this problem that has been useful in a variety of case studies, but its proteomic scale application is partially hindered because automated retrieval of input sequences from databases often includes some with errors that degrade functional site identification. To recognize and purge these sequences, this study introduces a novel and structure-free measure of ET quality called rank information (RI). It is shown that RI decreases in response to errors in sequences, alignments, or functional classifications. Conversely, an automated procedure to increase RI by selectively removing sequences improves functional site identification so as to nearly match manually curated traces in kinases and in a test set of 79 diverse proteins. Thus we conclude that RI partially reflects the evolutionary consistency of sequence, structure, and function. In practice, as the size of the proteome continues to grow exponentially, it provides a novel and structure-free measure of ET quality that increases its accuracy for large-scale automated annotation of protein functional sites.

Algorithms↗

PubMed2000

Sensitive sequence comparison as protein function predictor.

Protein function assignments based on postulated homology as recognized by high sequence similarity are used routinely in genome analysis. Improvements in sensitivity of sequence comparison algorithms got to the point, that proteins with previously undetectable sequence similarity, such as for instance 10-15% of identical residues, sometimes can be classified as similar. What is the relation between such proteins? Is it possible that they are homologous? What is the practical significance of detecting such similarities? A simplified analysis of the relation between sequence similarity and function similarity is presented here for the well-characterized proteins from the E. coli genome. Using a simple measure of functional similarity based on E.C. classification of enzymes, it is shown that it correlates well with sequence similarity measured by statistical significance of the alignment score. Proteins, similar by this standard, even in cases of low sequence identity, have a much larger chance of having similar function than the randomly chosen protein pairs. Interesting exceptions to these rules are discussed.

Algorithms↗

PubMed2002

The effects of phosphorylation on adaptor protein function.

Adaptor proteins are specialized protein binding partners that serve to link signaling proteins to each other, as a mechanism to propagate a cellular signal. Ultimately, these signals are required for a specific biological response. Thus, it is important that the cell develop mechanisms to regulate these signaling cascades. One way these cascades can be regulated is through post translational modifications of adaptor proteins which would regulate their ability to forge protein-protein interactions. In this review, we summarize the effects of serine/threonine and tyrosine phosphorylation on adaptor protein function, with a specific focus upon those adaptor proteins in which phosphorylation has been demonstrated to regulate a signaling cascade or biological response.

Animals↗

PubMed2006

A traveling salesman approach for predicting protein functions.

BACKGROUND: Protein-protein interaction information can be used to predict unknown protein functions and to help study biological pathways. RESULTS: Here we present a new approach utilizing the classic Traveling Salesman Problem to study the protein-protein interactions and to predict protein functions in budding yeast Saccharomyces cerevisiae. We apply the global optimization tool from combinatorial optimization algorithms to cluster the yeast proteins based on the global protein interaction information. We then use this clustering information to help us predict protein functions. We use our algorithm together with the direct neighbor algorithm 1 on characterized proteins and compare the prediction accuracy of the two methods. We show our algorithm can produce better predictions than the direct neighbor algorithm, which only considers the immediate neighbors of the query protein. CONCLUSION: Our method is a promising one to be used as a general tool to predict functions of uncharacterized proteins and a successful sample of using computer science knowledge and algorithms to study biological problems.

Journal Article↗

PubMed1993

Negative co-dominant inhibition of recA protein function. Biochemical properties of the recA1, recA13 and recA56 proteins and the effect of recA56 protein on the activities of the wild-type recA protein function in vitro.

We have investigated the biochemical properties of several Escherichia coli mutant recA proteins that display a null phenotype. These are the recA1, recA13 and recA56 proteins, each of which carries a single missense mutation. These proteins all share a common defect which is the inability to adopt the high affinity DNA binding state normally elicited by the nucleotide cofactor ATP. Consequently, other than the ability to bind ssDNA, they possess none of the in vitro enzymatic activities of recA protein. However, each protein has characteristics that are unique, leading to the conclusion that the observed mutant phenotypes arise through fundamentally different mechanisms. Despite the magnitude of these defects, the recA56 protein is able to differentially inhibit various activities of wild-type recA protein. Incorporation of recA56 protein into a presynaptic filament with the wild-type recA protein does not affect the ability of the wild-type protein to hydrolyze ATP, as judged by the turnover number (kcat), provided that the ssDNA concentration is not limiting; however, the affinity of wild-type recA protein for ATP is lowered by the presence of recA56 protein. Similarly, the ability to cleave lexA protein is only modestly inhibited. However, both the ability to compete with SSB protein for ssDNA binding sites and the DNA strand exchange activity of wild-type recA protein are severely inhibited by the presence of recA56 protein. These results suggest that individual monomeric components of the recA protein-DNA filament are translated through protein-protein contacts to become macroscopic properties of the filament.

Adenosine Diphosphate↗

PubMed2005

Applications of ancestral protein reconstruction in understanding protein function: GFP-like proteins.

Recreating ancestral proteins in the laboratory increasingly is being used to study the evolutionary history of protein function. More efficient gene synthesis techniques and the decreasing costs of commercial oligosynthesis are making this approach both simpler and less expensive to perform. Developments in ancestral reconstruction methods, particularly more realistic likelihood models of molecular evolution, allow for the accurate reconstruction of more ancient proteins than previously possible. This chapter reviews phylogenetic methods of ancestral inference, strategies for investigating alternative reconstructions, gene synthesis, and design, and an application of these methods to the reconstruction of an ancestor in the green fluorescent protein family.

Amino Acid Sequence↗

PubMed2005

Pattern recognition methods for protein functional site prediction.

Protein functional site prediction is closely related to drug design, hence to public health. In order to save the cost and the time spent on identifying the functional sites in sequenced proteins in biology laboratory, computer programs have been widely used for decades. Many of them are implemented using the state-of-the-art pattern recognition algorithms, including decision trees, neural networks and support vector machines. Although the success of this effort has been obvious, advanced and new algorithms are still under development for addressing some difficult issues. This review will go through the major stages in developing pattern recognition algorithms for protein functional site prediction and outline the future research directions in this important area.

Algorithms↗

PubMed1999

Assigning protein functions by comparative genome analysis: protein phylogenetic profiles.

Determining protein functions from genomic sequences is a central goal of bioinformatics. We present a method based on the assumption that proteins that function together in a pathway or structural complex are likely to evolve in a correlated fashion. During evolution, all such functionally linked proteins tend to be either preserved or eliminated in a new species. We describe this property of correlated evolution by characterizing each protein by its phylogenetic profile, a string that encodes the presence or absence of a protein in every known genome. We show that proteins having matching or similar profiles strongly tend to be functionally linked. This method of phylogenetic profiling allows us to predict the function of uncharacterized proteins.

Bacterial Proteins↗

PubMed1999

Detecting protein function and protein-protein interactions from genome sequences.

A computational method is proposed for inferring protein interactions from genome sequences on the basis of the observation that some pairs of interacting proteins have homologs in another organism fused into a single protein chain. Searching sequences from many genomes revealed 6809 such putative protein-protein interactions in Escherichia coli and 45,502 in yeast. Many members of these pairs were confirmed as functionally related; computational filtering further enriches for interactions. Some proteins have links to several other proteins; these coupled links appear to represent functional interactions such as complexes or pathways. Experimentally confirmed interacting pairs are documented in a Database of Interacting Proteins.

Amino Acid Sequence↗

PubMed1996

Functional domains in protein TrwC of plasmid R388: dissected DNA strand transferase and DNA helicase activities reconstitute protein function.

TrwC is a bifunctional enzyme that displays two biochemical activities essential for plasmid R388 conjugation: oriT-specific DNA strand-transferase and DNA helicase activities. We overproduced and purified different segments of the protein allowing us to map the relaxase and DNA helicase activities to separate regions of the protein. A peptide comprising the N-terminal 275 amino acid residues of the protein was able to catalyze DNA cleavage and strand-transfer reactions when using oligonucleotides encompassing the nic site, although a longer fragment of TrwC (348 amino acid residues) was required to produce the nick on a supercoiled double-stranded DNA substrate. The segment of the protein between amino acid residues 192 and 966 contained the ATPase and DNA helicase activities, while a peptide consisting of amino acid residues 346 to 966 lost both activities. The dimerization region lay in the 495 C-terminal amino acid residues. Two peptides containing the DNA strand-transferase and DNA helicase activities, respectively, could functionally substitute for TrwC in R388 conjugation although at a 10,000-fold lower efficiency. Thus, integrity of the covalent structure of the protein was required for efficient DNA transfer. It can be assumed that the covalent linkage increases the efficiency of conjugation by increasing the effective concentration of one component (presumably the DNA helicase) at its site of action.

Base Sequence↗

PubMed2000

Expression in Escherichia coli of N- and C-terminally deleted human holocarboxylase synthetase. Influence of the N-terminus on biotinylation and identification of a minimum functional protein.

Biotin functions as a covalently bound cofactor of biotindependent carboxylases. Biotin attachment is catalyzed by biotin protein ligases, called holocarboxylase synthetase in mammals and BirA in prokaryotes. These enzymes show a high degree of sequence similarity in their biotinylation domains but differ markedly in the length and sequence of their N terminus. BirA is also the repressor of the biotin operon, and its DNA attachment site is located in its N terminus. The function of the eukaryotic N terminus is unknown. Holocarboxylase synthetase with N- and C-terminal deletions were evaluated for the ability to catalyze biotinylation after expression in Escherichia coli using bacterial and human acceptor substrates. We showed that the minimum functional protein is comprised of the last 349 of the 726-residue protein, which includes the biotinylation domain. Significantly, enzyme containing intermediate length, N-terminal deletions interfered with biotin transfer and interaction with different peptide acceptor substrates. We propose that the N terminus of holocarboxylase synthetase contributes to biotinylation through N- and C-terminal interactions and may affect acceptor substrate recognition. Our findings provide a rationale for the biotin responsiveness of patients with point mutations in the N-terminal sequence of holocarboxylase synthetase. Such mutant enzyme may respond to biotin-mediated stabilization of the substrate-bound complex.

Base Sequence↗