Yeast Protein-protein Interaction Research Articles

A cell-core-attachment approach for identifying protein complexes in yeast protein-protein interaction network

With the increasing of available protein-protein interaction (PPI) data, many computational methods have been explored to identify protein complexes from PPI networks. Majority of algorithms employ the feature of local neighbors to detect local dense subgraphs which correspond to protein complexes. Those approaches neglect the inherent core-attachment structure of protein complexes, which to an extent affect the protein complexes of prediction accuracy. In this paper, we propose a new algorithm for predicting protein complexes, deriving from the framework of the core-attachment. The proposed method first obtains the triangular structures of the core of protein complexes, name as cells, in which the edge-clustering coefficient is used. And then the cells are expanded to protein complex cores based on the closeness. Finally, the attachments are added to their corresponding cores to form the final protein complexes. The experimental results on two yeast PPI data show our method outperform the existing algorithms in terms of matched protein complexes and biological significance using two benchmark data sets.

Improving analytical methods for protein-protein interaction through implementation of chemically inducible dimerization.

When investigating interactions between two proteins with complementary reporter tags in yeast two-hybrid or split GFP assays, it remains troublesome to discriminate true- from false-negative results and challenging to compare the level of interaction across experiments. This leads to decreased sensitivity and renders analysis of weak or transient interactions difficult to perform. In this work, we describe the development of reporters that can be chemically induced to dimerize independently of the investigated interactions and thus alleviate these issues. We incorporated our reporters into the widely used split ubiquitin-, bimolecular fluorescence complementation (BiFC)- and Förster resonance energy transfer (FRET)- based methods and investigated different protein-protein interactions in yeast and plants. We demonstrate the functionality of this concept by the analysis of weakly interacting proteins from specialized metabolism in the model plant Arabidopsis thaliana. Our results illustrate that chemically induced dimerization can function as a built-in control for split-based systems that is easily implemented and allows for direct evaluation of functionality.

Predicting physiologically relevant SH3 domain mediated protein-protein interactions in yeast.

Motivation: Many intracellular signaling processes are mediated by interactions involving peptide recognition modules such as SH3 domains. These domains bind to small, linear protein sequence motifs which can be identified using high-throughput experimental screens such as phage display. Binding motif patterns can then be used to computationally predict protein interactions mediated by these domains. While many protein–protein interaction prediction methods exist, most do not work with peptide recognition module mediated interactions or do not consider many of the known constraints governing physiologically relevant interactions between two proteins.Results: A novel method for predicting physiologically relevant SH3 domain-peptide mediated protein–protein interactions in S. cerevisae using phage display data is presented. Like some previous similar methods, this method uses position weight matrix models of protein linear motif preference for individual SH3 domains to scan the proteome for potential hits and then filters these hits using a range of evidence sources related to sequence-based and cellular constraints on protein interactions. The novelty of this approach is the large number of evidence sources used and the method of combination of sequence based and protein pair based evidence sources. By combining different peptide and protein features using multiple Bayesian models we are able to predict high confidence interactions with an overall accuracy of 0.97.Availability and implementation: Domain-Motif Mediated Interaction Prediction (DoMo-Pred) command line tool and all relevant datasets are available under GNU LGPL license for download from http://www.baderlab.org/Software/DoMo-Pred. The DoMo-Pred command line tool is implemented using Python 2.7 and C ++.Contact: gary.bader@utoronto.caSupplementary information: Supplementary data are available at Bioinformatics online.

Use of the BioGRID Database for Analysis of Yeast Protein and Genetic Interactions.

The BioGRID database is an extensive repository of curated genetic and protein interactions for the budding yeast Saccharomyces cerevisiae, the fission yeast Schizosaccharomyces pombe, and the yeast Candida albicans SC5314, as well as for several other model organisms and humans. This protocol describes how to use the BioGRID website to query genetic or protein interactions for any gene of interest, how to visualize the associated interactions using an embedded interactive network viewer, and how to download data files for either selected interactions or the entire BioGRID interaction data set.

Positive Selection and Centrality in the Yeast and Fly Protein-Protein Interaction Networks.

Proteins within a molecular network are expected to be subject to different selective pressures depending on their relative hierarchical positions. However, it is not obvious what genes within a network should be more likely to evolve under positive selection. On one hand, only mutations at genes with a relatively high degree of control over adaptive phenotypes (such as those encoding highly connected proteins) are expected to be “seen” by natural selection. On the other hand, a high degree of pleiotropy at these genes is expected to hinder adaptation. Previous analyses of the human protein-protein interaction network have shown that genes under long-term, recurrent positive selection (as inferred from interspecific comparisons) tend to act at the periphery of the network. It is unknown, however, whether these trends apply to other organisms. Here, we show that long-term positive selection has preferentially targeted the periphery of the yeast interactome. Conversely, in flies, genes under positive selection encode significantly more connected and central proteins. These observations are not due to covariation of genes' adaptability and centrality with confounding factors. Therefore, the distribution of proteins encoded by genes under recurrent positive selection across protein-protein interaction networks varies from one species to another.

Prediction of Essential Proteins Based on Local Interaction Density.

Prediction of essential proteins which is aided by computer science and supported from high throughput data is a more efficient method compared with time consuming and expensive experimental approaches. There are many computational approaches reported, however they are usually sensitive to various network structures so that their robustness are generally poor. In this paper, a novel topological centrality measure for predicting essential proteins based on local interaction density, named as LID, is proposed. It is different from previous measures that LID takes the essentiality of a node from interaction densities among its neighbors through topological analyses of real proteins in a protein complex set first time at the viewpoint of biological modules. LID is applied to four different yeast protein interaction networks, which are obtained, respectively, from the DIP database and the BioGRID database. The experimental results show that the number of essential proteins detected by LID universally exceeds or approximates the best performance of other 10 topological centrality measures in all 24 comparisons of four networks: DC, BC, ClusterC, CloseC, MNC, SoECC(NC), LAC, SC, EigC, and InfoC. The better robustness of LID for multiple data sets will make it to be a new core topological centrality measure to improve the performance of prediction for more species protein interaction networks.

Multi-scale perturbations of protein interactomes reveal their mechanisms of regulation, robustness and insights into genotype-phenotype maps.

Cellular architectures and signaling machineries are organized through protein-protein interactions (PPIs). High-throughput methods to study PPIs in yeast have opened a new perspective on the organization of the cell by allowing the study of whole protein interactomes. Recent investigations have moved from the description of this organization to the analysis of its dynamics by experimenting how protein interaction networks (PINs) are rewired in response to perturbations. Here we review studies that have used the budding yeast as an experimental system to explore these altered networks. Given the large space of possible PPIs and the diversity of potential genetic and environmental perturbations, high-throughput methods are an essential requirement to survey PIN perturbations on a large scale. Network perturbations are typically conceptualized as the removal of entire proteins (nodes), the modification of single PPIs (edges) or changes in growth conditions. These studies have revealed mechanisms of PPI regulation, PIN architectural organization, robustness and sensitivity to perturbations. Despite these major advances, there are still inherent limits to current technologies that lead to a trade-off between the number of perturbations and the number of PPIs that can be considered simultaneously. Nevertheless, as we exemplify here, targeted approaches combined with the existing resources remain extremely powerful to explore the inner organization of cells and their responses to perturbations.

Structural basis of pathogen recognition by an integrated HMA domain in a plant NLR immune receptor.

Plants have evolved intracellular immune receptors to detect pathogen proteins known as effectors. How these immune receptors detect effectors remains poorly understood. Here we describe the structural basis for direct recognition of AVR-Pik, an effector from the rice blast pathogen, by the rice intracellular NLR immune receptor Pik. AVR-PikD binds a dimer of the Pikp-1 HMA integrated domain with nanomolar affinity. The crystal structure of the Pikp-HMA/AVR-PikD complex enabled design of mutations to alter protein interaction in yeast and in vitro, and perturb effector-mediated response both in a rice cultivar containing Pikp and upon expression of AVR-PikD and Pikp in the model plant Nicotiana benthamiana. These data reveal the molecular details of a recognition event, mediated by a novel integrated domain in an NLR, which initiates a plant immune response and resistance to rice blast disease. Such studies underpin novel opportunities for engineering disease resistance to plant pathogens in staple food crops.

Monte Carlo Algorithms for Identifying Densely Connected Subgraphs

The problem of finding densely connected subgraphs in a network has attracted a lot of recent interest. Such subgraphs are sometimes referred to as communities in social networks or molecular modules in protein networks. In this article, we propose two Monte Carlo optimization algorithms for identifying the densest subgraphs with a fixed size or with size in a given range. The new algorithms combine the idea of simulated annealing and efficient moves for the Markov chain, and both algorithms are shown to converge to the set of optimal states (densest subgraphs) with probability 1. When applied to a yeast protein interaction network and a stock market graph, the algorithms identify interesting new densely connected subgraphs. Supplementary materials for the article are available online.

Yeast protein-protein interaction network model based on biological experimental data

Duplication and divergence have been widely recognized as the two dominant evolutionary forces in shaping biological networks, e.g., gene regulatory networks and protein-protein interaction (PPI) networks. It has been shown that the network growth models constructed on the principle of duplication and divergence can recapture the topological properties of real PPI networks. However, such network models only consider the evolution processes. How to select the model parameters with the real biological experimental data has not been presented. Therefore, based on the real PPI network statistical data, a yeast PPI network model is constructed. The simulation results indicate that the topological characteristics of the constructed network model are well consistent with those of real PPI networks, especially on sparseness, scale-free, small-world, hierarchical modularity, and disassortativity.

Analyzing complex networks through correlations in centrality measurements

Many real world systems can be expressed as complex networks of interconnected nodes. It is frequently important to be able to quantify the relative importance of the various nodes in the network, a task accomplished by defining some centrality measures, with different centrality definitions stressing different aspects of the network. It is interesting to know to what extent these different centrality definitions are related for different networks. In this work, we study the correlation between pairs of a set of centrality measures for different real world networks and two network models. We show that the centralities are in general correlated, but with stronger correlations for network models than for real networks. We also show that the strength of the correlation of each pair of centralities varies from network to network. Taking this fact into account, we propose the use of a centrality correlation profile, consisting of the values of the correlation coefficients between all pairs of centralities of interest, as a way to characterize networks. Using the yeast protein interaction network as an example we show also that the centrality correlation profile can be used to assess the adequacy of a network model as a representation of a given real network.

Overlap maximum matching ratio (OMMR): a new measure to evaluate overlaps of essential modules

Protein complexes are the basic units of macro-molecular organizations and help us to understand the cell’s mechanism. The development of the yeast two-hybrid, tandem affinity purification, and mass spectrometry high-throughput proteomic techniques supplies a large amount of protein-protein interaction data, which make it possible to predict overlapping complexes through computational methods. Research shows that overlapping complexes can contribute to identifying essential proteins, which are necessary for the organism to survive and reproduce, and for life’s activities. Scholars pay more attention to the evaluation of protein complexes. However, few of them focus on predicted overlaps. In this paper, an evaluation criterion called overlap maximum matching ratio (OMMR) is proposed to analyze the similarity between the identified overlaps and the benchmark overlap modules. Comparison of essential proteins and gene ontology (GO) analysis are also used to assess the quality of overlaps. We perform a comprehensive comparison of serveral overlapping complexes prediction approaches, using three yeast protein-protein interaction (PPI) networks. We focus on the analysis of overlaps identified by these algorithms. Experimental results indicate the important of overlaps and reveal the relationship between overlaps and identification of essential proteins.

Modularity in the evolution of yeast protein interaction network.

Protein interaction networks are known to exhibit remarkable structures: scale-free and small-world and modular structures. To explain the evolutionary processes of protein interaction networks possessing scale-free and small-world structures, preferential attachment and duplication-divergence models have been proposed as mathematical models. Protein interaction networks are also known to exhibit another remarkable structural characteristic, modular structure. How the protein interaction networks became to exhibit modularity in their evolution? Here, we propose a hypothesis of modularity in the evolution of yeast protein interaction network based on molecular evolutionary evidence. We assigned yeast proteins into six evolutionary ages by constructing a phylogenetic profile. We found that all the almost half of hub proteins are evolutionarily new. Examining the evolutionary processes of protein complexes, functional modules and topological modules, we also found that member proteins of these modules tend to appear in one or two evolutionary ages. Moreover, proteins in protein complexes and topological modules show significantly low evolutionary rates than those not in these modules. Our results suggest a hypothesis of modularity in the evolution of yeast protein interaction network as systems evolution.

Evolutionary and functional analysis of the invariant SWIM domain in the conserved Shu2/SWS1 protein family from Saccharomyces cerevisiae to Homo sapiens.

The Saccharomyces cerevisiae Shu2 protein is an important regulator of Rad51, which promotes homologous recombination (HR). Shu2 functions in the Shu complex with Shu1 and the Rad51 paralogs Csm2 and Psy3. Shu2 belongs to the SWS1 protein family, which is characterized by its SWIM domain (CXC...Xn...CXH), a zinc-binding motif. In humans, SWS1 interacts with the Rad51 paralog SWSAP1. Using genetic and evolutionary analyses, we examined the role of the Shu complex in mitotic and meiotic processes across eukaryotic lineages. We provide evidence that the SWS1 protein family contains orthologous genes in early-branching eukaryote lineages (e.g., Giardia lamblia), as well as in multicellular eukaryotes including Caenorhabditis elegans and Drosophila melanogaster. Using sequence analysis, we expanded the SWIM domain to include an invariant alanine three residues after the terminal CXH motif (CXC…Xn…CXHXXA). We found that the SWIM domain is conserved in all eukaryotic orthologs, and accordingly, in vivo disruption of the invariant residues within the canonical SWIM domain inhibits DNA damage tolerance in yeast and protein-protein interactions in yeast and humans. Furthermore, using evolutionary analyses, we found that yeast and Drosophila Shu2 exhibit strong coevolutionary signatures with meiotic proteins, and in yeast, its disruption leads to decreased meiotic progeny. Together our data indicate that the SWS1 family is an ancient and highly conserved eukaryotic regulator of meiotic and mitotic HR.

A new algorithm for essential proteins identification based on the integration of protein complex co-expression information and edge clustering coefficient.

Essential proteins provide valuable information for the development of biology and medical research from the system level. The accuracy of topological centrality only based methods is deeply affected by noise in the network. Therefore, exploring efficient methods for identifying essential proteins would be of great value. Using biological features to identify essential proteins is efficient in reducing the noise in PPI network. In this paper, based on the consideration that essential proteins evolve slowly and play a central role within a network, a new algorithm, named CED, is proposed. CED mainly employs gene expression level, protein complex information and edge clustering coefficient to predict essential proteins. The performance of CED is validated based on the yeast Protein-Protein Interaction (PPI) network obtained from DIP database and BioGRID database. The prediction accuracy of CED outperforms other seven algorithms when applied to the two databases.

Cross-disciplinary detection and analysis of network motifs.

The detection of network motifs has recently become an important part of network analysis across all disciplines. In this work, we detected and analyzed network motifs from undirected and directed networks of several different disciplines, including biological network, social network, ecological network, as well as other networks such as airlines, power grid, and co-purchase of political books networks. Our analysis revealed that undirected networks are similar at the basic three and four nodes, while the analysis of directed networks revealed the distinction between networks of different disciplines. The study showed that larger motifs contained the three-node motif as a subgraph. Topological analysis revealed that similar networks have similar small motifs, but as the motif size increases, differences arise. Pearson correlation coefficient showed strong positive relationship between some undirected networks but inverse relationship between some directed networks. The study suggests that the three-node motif is a building block of larger motifs. It also suggests that undirected networks share similar low-level structures. Moreover, similar networks share similar small motifs, but larger motifs define the unique structure of individuals. Pearson correlation coefficient suggests that protein structure networks, dolphin social network, and co-authorships in network science belong to a superfamily. In addition, yeast protein–protein interaction network, primary school contact network, Zachary’s karate club network, and co-purchase of political books network can be classified into a superfamily.

CPL: Detecting Protein Complexes by Propagating Labels on Protein-Protein Interaction Network

Proteins usually bind together to form complexes, which play an important role in cellular activities. Many graph clustering methods have been proposed to identify protein complexes by finding dense regions in protein-protein interaction networks. We present a novel framework (CPL) that detects protein complexes by propagating labels through interactions in a network, in which labels denote complex identifiers. With proper propagation in CPL, proteins in the same complex will be assigned with the same labels. CPL does not make any strong assumptions about the topological structures of the complexes, as in previous methods. The CPL algorithm is tested on several publicly available yeast protein-protein interaction networks and compared with several state-of-the-art methods. The results suggest that CPL performs better than the existing methods. An analysis of the functional homogeneity based on a gene ontology analysis shows that the detected complexes of CPL are highly biologically relevant.

Identification of Important Proteins in Protein Interaction Network Based on SVM

Importance of proteins are different to perform functions of cells in living organisms according to the relevant experiment results, and more essential proteins is the most important kind of proteins. There are recently many computational approaches proposed to predict essential proteins in network level through network topologies combined with biological information of proteins. However it is still hard to identify them because of limitations of topological centralities and bioinformatic sources. And more it is the challenge is to perform better with less resources. Therefore in this paper, we first examine the correlation between common topological centralities and essential proteins and choose a few particular centralities, and then to build a SVM model, names as TC-SVM, for predicting the essential proteins. The new method has been applied to a yeast protein interaction networks, which are obtained from the BioGRID database. The ten folds experimental results show that the performance of predicting essential proteins by TC-SVM is excellent.

The yeast protein interaction network has a capacity for self-organization.

The organization of the cellular interior gives rise to properties including metabolic channeling and micro-compartmentalization of signaling. Here, we use a lattice model of molecular crowding, together with literature-derived protein interactions and abundances, to describe the molecular organization and stoichiometry of local cellular regions, showing that physical protein-protein interactions induce emergent structures not seen when random interaction networks are modeled. Specifically, we find that the lattices give rise to micro-groups of enzymes on the surfaces of protein clusters. These arrangements of proteins are also robust to protein overexpression, while still showing evidence for expression tuning. Our results indicate that some of the complex organization of the cell may derive from simple rules of molecular aggregation and interaction.

Controllability in protein interaction networks.

Recently, the focus of network research shifted to network controllability, prompting us to determine proteins that are important for the control of the underlying interaction webs. In particular, we determined minimum dominating sets of proteins (MDSets) in human and yeast protein interaction networks. Such groups of proteins were defined as optimized subsets where each non-MDSet protein can be reached by an interaction from an MDSet protein. Notably, we found that MDSet proteins were enriched with essential, cancer-related, and virus-targeted genes. Their central position allowed MDSet proteins to connect protein complexes and to have a higher impact on network resilience than hub proteins. As for their involvement in regulatory functions, MDSet proteins were enriched with transcription factors and protein kinases and were significantly involved in bottleneck interactions, regulatory links, phosphorylation events, and genetic interactions.