Changes in the abundance of protein and RNA molecules can impair the formation of complexes in the cell leading to toxicity and death. Here we exploit the information contained in protein, RNA and DNA interaction networks to provide a comprehensive view of the regulation layers controlling the concentration‐dependent formation of assemblies in the cell. We present the emerging concept that RNAs can act as scaffolds to promote the formation ribonucleoprotein complexes and coordinate the post‐transcriptional layer of gene (...) regulation. We describe the structural and interaction network properties that characterize the ability of protein and RNA molecules to interact and phase separate in liquid‐like compartments. Finally, we show that presence of structurally disordered regions in proteins correlate with the propensity to undergo liquid‐to‐solid phase transitions and cause human diseases. Also see the video abstract here https://youtu.be/kfpqibsNfS0. (shrink)

The emerging area of network biology is seeking to provide insights into organizational principles of life. However, despite significant collaborative efforts, there is still typically a weak link between biological and computational scientists and a lack of understanding of the research issues across the disciplines. This results in the use of simple computational techniques of limited potential that are incapable of explaining these complex data. Hence, the danger is that the community might begin to view the topological properties of network (...) data as mere statistics, rather than rich sources of biological information. A further danger is that such views might result in the imposition of scientific doctrines, such as scale-free-centric (on the modeling side) and genome-centric (on the biological side) opinions onto this area. Here, we take a graph-theoretic perspective on protein-protein interaction networks and present a high-level overview of the area, commenting on possible challenges ahead. (shrink)

A general framework by which dynamic interactions within a protein will promote the necessary series of structural changes, or “conformational cycle,” required for function is proposed. It is suggested that the free‐energy landscape of a protein is biased toward this conformational cycle. Fluctuations into higher energy, although thermally accessible, conformations drive the conformational cycle forward. The amino acid interaction network is defined as those intraprotein interactions that contribute most to the free‐energy landscape. Some network connections are consistent in (...) every structural state, while others periodically change their interaction strength according to the conformational cycle. It is reviewed here that structural transitions change these periodic network connections, which then predisposes the protein toward the next set of network changes, and hence the next structural change. These concepts are illustrated by recent work on tryptophan synthase. Disruption of these dynamic connections may lead to aberrant protein function and disease states. (shrink)

The Protein Ontology (PRO; http://proconsortium.org) formally defines protein entities and explicitly represents their major forms and interrelations. Protein entities represented in PRO corresponding to single amino acid chains are categorized by level of specificity into family, gene, sequence and modification metaclasses, and there is a separate metaclass for protein complexes. All metaclasses also have organism-specific derivatives. PRO complements established sequence databases such as UniProtKB, and interoperates with other biomedical and biological ontologies such as the Gene Ontology (...) (GO). PRO relates to UniProtKB in that PRO’s organism-specific classes of proteins encoded by a specific gene correspond to entities documented in UniProtKB entries. PRO relates to the GO in that PRO’s representations of organism-specific protein complexes are subclasses of the organism-agnostic protein complex terms in the GO Cellular Component Ontology. The past few years have seen growth and changes to the PRO, as well as new points of access to the data and new applications of PRO in immunology and proteomics. Here we describe some of these developments. (shrink)

There is an urgent need for novel protection strategies to sustainably secure crop production under changing climates. Studying microbial effectors, defined as microbe‐derived proteins that alter signalling inside plant cells, has advanced our understanding of plant immunity and microbial plant colonisation strategies. Our understanding of effectors in the establishment and beneficial outcome of plant symbioses is less well known. Combining functional and comparative interaction assays uncovered specific symbiont effector targets in highly interconnected plant signalling networks and revealed the potential (...) of effectors in beneficially modulating plant traits. The diverse functionality of symbiont effectors differs from the paradigmatic immuno‐suppressive function of pathogen effectors. These effectors provide solutions for improving crop resilience against climate stress by their evolution‐driven specification in host protein targeting and modulation. Symbiont effectors represent stringent tools not only to identify genetic targets for crop breeding, but to serve as applicable agents in crop management strategies under changing environments. (shrink)

Comprehensive analysis of proteins to evaluate their genetic diversity, study their differences, and respond to the tensions is the main subject of an interdisciplinary field of study called proteomics. The main objective of the proteomics is to detect and quantify proteins and study their post-translational modifications and interactions using protein chemistry, bioinformatics, and biology. Any disturbance in proteins interactive network can act as a source for biological disorders and various diseases such as Alzheimer and cancer. Most current computational methods (...) for discovering protein complexes are usually based on specific topological characteristics of protein-protein networks. To identify the protein complexes, in this paper, we, first, present a new encoding method to represent solutions; we then propose a new clustering algorithm based on the genetic algorithm, named PPI-GA, employing a new multiobjective quality function. The proposed algorithm is evaluated on two gold standard and real-world datasets. The result achieved demonstrates that the proposed algorithm can detect important protein complexes, and it provides more accurate results compared with state-of-the-art protein complex identification algorithms. (shrink)

In this post‐sequencing era, geneticists can focus on functional genomics on a much larger scale than ever before. One goal is the discovery and elucidation of the intricate genetic networks that co‐ordinate transcriptional activation in different regulatory circuitries. High‐throughput gene expression measurement using DNA arrays has thus become routine strategy. This approach, however, does not directly identify gene loci that belong to the same regulatory group; e.g., those that are bound by a common (set of) transcription factor(s). Working in (...) yeast, two groups have recently published an elegant method that could circumvent this problem, by combining chromatin immunoprecipitation and DNA microarrays.(1,2) The method is likely to provide a powerful tool for the dissection of global regulatory networks in eukaryotic cells. BioEssays 23:473–476, 2001. © 2001 John Wiley & Sons, Inc. (shrink)

Signaling complexes and networks are being intensely studied in an attempt to discover pathways that are amenable to therapeutic intervention. A challenge in this search is to understand the effect that the modulation of a target will have on the overall function of a cell and its surrounding neighbors. Protein‐interaction mapping reveals relationships between proteins and their impact on cellular processes and is being used more widely in our understanding of disease mechanisms and their treatment. The review discusses (...) challenges and breakthroughs in this new and evolving area and its impact on medicine. BioEssays 27:958–969, 2005. © 2005 Wiley Periodicals, Inc. (shrink)

Systems biology provides alternatives to the strategies to developing mechanistic explanations traditionally pursued in cell and molecular biology and much discussed in accounts of mechanistic explanation. Rather than starting by identifying a mechanism for a given phenomenon and decomposing it, systems biologists often start by developing cell-wide networks of detected connections between proteins or genes and construe clusters of highly interactive components as potential mechanisms. Using inference strategies such as ‘guilt-by-association’, researchers advance hypotheses about functions performed of these mechanisms. (...) I examine several examples of research on budding yeast, first on what are taken to be enduring networks and subsequently on networks that change as cells perform different activities or respond to different external conditions. (shrink)

Regulated secretory proteins are stored within specialized vesicles known as secretory granules. It is not known how proteins are sorted into these organelles. Regulated proteins may possess targeting signals which interact with specific sorting receptors in the lumen of the trans‐Golgi network (TGN) prior to their aggregation to form the characteristic dense‐core of the granule. Alternatively, sorting may occur as the result of specific aggregation of regulated proteins in the TGN. Aggregates may be directed to secretory granules by interaction of (...) a targeting signal on the surface with a sorting receptor. Novel targeting signals which confer on regulated proteins a tendency to aggregate under certain conditions, and in so doing cause them to be incorporated into secretory granules, have been implicated. Specific targeting signals may also play a role in directing membrane proteins to secretory granules. (shrink)

Recent experimental data from proteomics and genomics are interpreted here in ways that challenge the predominant viewpoint in biology according to which the four evolutionary processes, including mutation, recombination, natural selection and genetic drift, are sufficient to explain the origination of species. The predominant viewpoint appears incompatible with the finding that the sequenced genome of each species contains hundreds, or even thousands, of unique genes - the genes that are not shared with any other species. These unique genes and proteins, (...) singletons, define the very character of every species. Moreover, the distribution of protein families from the sequenced genomes indicates that the complexity of genomes grows in a manner different from that of self-organizing networks: the dominance of singletons leads to the conclusion that in living organisms a most unlikely phenomenon can be the most common one. In order to provide proper rationale for these conclusions related to the singletons, the paper first treats the frequency of functional proteins among random sequences, followed by a discussion on the protein structure space, and it ends by questioning the idea that protein domains represent conserved units of evolution. (shrink)

A protein kinase cascade is involved in the action of some mitogens. The cascade begins with receptor tyrosine kinase activation by growth factors. The resulting signal is transmitted into cells via phospholipid metabolism which produces a variety of second messengers and by intracellular protein kinase activation. The signal is then propagated and disseminated via a network of other proteln kinases and protein phosphatases. Recent research suggests that ribosomal protein S6 kinase and casein kinase II are two (...) important elements in the kinase cascade that leads to the initiation of growth. The nature and some properties of these hitherto lesser known enzymes is considered. (shrink)

Mechanical stimulation has a critical role in the development and maintenance of the skeleton. This function requires the perception of extracellular stimuli as well as their conversion into intracellular biochemical responses. This process is called mechanotransduction and is mediated by a plethora of molecular events that regulate bone metabolism. Indeed, mechanoreceptors, such as integrins, G protein‐coupled receptors, receptor protein tyrosine kinases, and stretch‐activated Ca2+ channels, together with their downstream effectors coordinate the transmission of load‐induced signals to the nucleus (...) and the expression of bone‐related genes. During the past decade, scientists have gained increasing insight into the molecular networks implicated in bone mechanotransduction. In the present paper, we consider the major signaling cascades and transcription factors that control bone and cartilage mechanobiology and discuss the influence of the mechanical microenvironment on the determination of skeletal morphology. (shrink)

Around 1960, leading figures in the international conservation circuit – such as Julian Huxley, Frank Fraser Darling and E. Barton Worthington – successfully propagated new visions about the value of undomesticated African mammals. Against traditional ideas, they presented these mammals as a highly efficient source of protein for growing African populations. In line with this vision, they challenged non-interventionist ideals of nature preservation, and launched proposals for active management through game ‘ranching’ and ‘cropping’. As such, they created a new (...) socio-technical imaginary for Africa's future, in which the consumption of wildlife meat took up a central position. This article explores the motivations of Western conservationists for this drastic rebranding. It argues that the rationale of considering African wildlife in terms of protein played an important symbolical role at various levels. It was crucial in the reorganization of the transnational networks of conservation, but also in the boosting of their scientific reputation, in the restructuring of their institutional ties, and in their attempts to maintain an authoritative position for Western ecologists in a rapidly decolonizing world. (shrink)

We provide an introduction to network theory, evidence to support a connection between molecular network structure and neuropsychiatric disease, and examples of how network approaches can expand our knowledge of the molecular bases of these diseases. Without systematic methods to derive their biological meanings and inter‐relatedness, the many molecular changes associated with neuropsychiatric disease, including genetic variants, gene expression changes, and protein differences, present an impenetrably complex set of findings. Network approaches can potentially help integrate and reconcile these findings, (...) as well as provide new insights into the molecular architecture of neuropsychiatric diseases. Network approaches to neuropsychiatric disease are still in their infancy, and we discuss what might be done to improve their prospects. (shrink)

Since its original identification as a component of the heterogeneous nuclear ribonucleoprotein (hnRNP) complex, K protein has been found not only in the nucleus but also in the cytoplasm and mitochondria and is implicated in chromatin remodeling, transcription, splicing and translation processes. K protein contains multiple modules that, on one hand, bind kinases while, on the other hand, recruit chromatin, transcription, splicing and translation factors. Moreover, the K‐ protein‐mediated interactions are regulated by signaling cascades. These observations are (...) consistent with K protein acting as a docking platform to integrate signaling cascades by facilitating cross‐talk between kinases and factors that mediate nucleic‐acid‐directed processes. Comparison of K across species reveals that it is an essential factor in metazoans, but not in yeast. Although some of the K protein interactions and functions are conserved in eukaryotes from yeast to man, the mammalian protein seems to play a wider role. The greater diversity of mammalian K protein interactions and function may reflect gain of novel docking sites and expansion evolutionary of gene expression networks. BioEssays 26:629–638, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

Secreted Frizzled‐related proteins (SFRPs) are modulators of the intermeshing pathways in which signals are transduced by Wnt ligands through Frizzled (Fz) membrane receptors. The Wnt networks influence biological processes ranging from developmental cell fate, cell polarity and adhesion to tumorigenesis and apoptosis. In the five or six years since their discovery, the SFRPs have emerged as dynamically expressed proteins able to bind both Wnts and Fz, with distinctive structural properties in which cysteine‐rich domains from Fz‐ and from netrin‐like proteins (...) are juxtaposed. The abundant expression of SFRP genes in the early embryo, altered expression patterns in disease states, and potential significance in the evolution of the vertebrate body plan, make these intriguing molecules relevant to investigations in diverse fields of biology and biomedical sciences. BioEssays 24:811–820, 2002. © 2002 Wiley Periodicals, Inc. (shrink)

I hypothesize that re-occurring prior experience of complex systems mobilizes a fast response, whose attractor is encoded by their strongly connected network core. In contrast, responses to novel stimuli are often slow and require the weakly connected network periphery. Upon repeated stimulus, peripheral network nodes remodel the network core that encodes the attractor of the new response. This “core-periphery learning” theory reviews and generalizes the heretofore fragmented knowledge on attractor formation by neural networks, periphery-driven innovation, and a number of (...) recent reports on the adaptation of protein, neuronal, and social networks. The core-periphery learning theory may increase our understanding of signaling, memory formation, information encoding and decision-making processes. Moreover, the power of network periphery-related “wisdom of crowds” inventing creative, novel responses indicates that deliberative democracy is a slow yet efficient learning strategy developed as the success of a billion-year evolution. Also see the video abstract here: https://youtu.be/IIjP7zWGjVE. The network core triggers fast responses to previously experienced stimuli. Innovations require the network periphery that encodes a novel attractor by core-remodeling. This core-periphery learning theory is introduced as a general adaptation, learning, decision-making, and forgetting mechanism of all complex systems including protein, metabolic, signaling, neuronal, social networks, and ecosystems. (shrink)

Cyclic adenosine monophosphate (cAMP) and cAMP‐dependent protein kinase A (PKA) are evolutionary conserved molecules with a well‐established position in the complex network of signal transduction pathways. cAMP/PKA‐mediated signaling pathways are implicated in many biological processes that cooperate in organ development including the motility, survival, proliferation and differentiation of epithelial cells. Cell surface polarity, here defined as the anisotropic organisation of cellular membranes, is a critical parameter for most of these processes. Changes in the activity of cAMP/PKA elicit a variety (...) of effects on intracellular membrane dynamics, including membrane sorting and trafficking. One of the most intriguing aspects of cAMP/PKA signaling is its evolutionary conserved abundance on the one hand and its precise spatial–temporal actions on the other. Here, we review recent developments with regard to the role of cAMP/PKA in the regulation of intracellular membrane trafficking in relation to the dynamics of epithelial surface domains. BioEssays 30:146–155, 2008. © 2008 Wiley Periodicals, Inc. (shrink)

How do common and rare genetic polymorphisms contribute to quantitative traits or disease risk and progression? Multiple human traits have been extensively characterized at the genomic level, revealing their complex genetic architecture. However, it is difficult to resolve the mechanisms by which specific variants contribute to a phenotype. Recently, analyses of variant effects on molecular traits have uncovered intermediate mechanisms that link sequence variation to phenotypic changes. Yet, these methods only capture a fraction of genetic contributions to phenotype. Here, in (...) reviewing the field, it is proposed that complex traits can be understood by characterizing the dynamics of biochemical networks within living cells, and that the effects of genetic variation can be captured on these networks by using protein–protein interaction (PPI) methodologies. This synergy between PPI methodologies and the genetics of complex traits opens new avenues to investigate the molecular etiology of human diseases and to facilitate their prevention or treatment. (shrink)

Lower plasma levels of high-density lipoproteins in adolescents with type 2 diabetes have been associated with a higher pulse wave velocity, a marker of arterial stiffness. Evidence suggests that HDL proteins or particle subspecies are altered in T2D and these may drive these relationships. In this work, we set out to reveal any specific proteins and subspecies that are related to arterial stiffness in youth with T2D from proteomics data. Plasma and PWV measurements were previously acquired from lean and T2D (...) adolescents. Each plasma sample was separated into 18 fractions and evaluated by mass spectrometry. Then, we applied a validated network-based computational approach to reveal HDL subspecies associated with PWV. Among 68 detected phospholipid-associated proteins, we found that seven were negatively correlated with PWV, indicating that they may be atheroprotective. Conversely, nine proteins show positive correlation with PWV, suggesting that they may be related to arterial stiffness. Intriguingly, our results demonstrate that apoA-I and histidine-rich glycoprotein may reverse their protective roles and become antagonistic in the setting of T2D. Furthermore, we revealed two arterial stiffness-associated HDL subspecies, each of which contains multiple PWV-related proteins. Correlation and disease association analyses suggest that these HDL subspecies might link T2D to its cardiovascular-related complications. (shrink)

The plasma membrane of polarized epithelial cells is divided into apical and basolateral surfaces, with different compositions. Proteins can be sent directly from the trans‐Golgi network (TGN) to either surface, or can be sent first to one surface and then transcytosed to the other. The glycosyl phosphatidylinositol anchor is a signal for apical targeting. Signals in the cytoplasmic domain containing a β‐turn determine basolateral targeting and retrieval, and are related to other sorting signals. Transcytosed proteins, such as the polymeric immunoglobulin (...) receptor (plgR), are endocytosed from the basolateral surface and then accumulate in a tubular compartment concentrated underneath the apical surface. This compartment, tentatively termed the apical recycling compartment, may be a central sorting station, as it apparently receives material from both surfaces and sorts them for delivery to the correct surface. Delivery to the apical surface from both the TGN and the apical recycling compartment appears to be regulated by protein kinases A and C, and endocytosis from the apical surface is also regulated by kinases. Transcytosis of the plgR is additionally regulated by phosphorylation of the plgR and by ligand binding to the plgR. Regulation of traffic in polarized epithelial cells plays a central role in cellular homeostasis, response to external signals and differentiation. (shrink)

Bioactive peptides are a group of diverse intercellular signalling molecules. Almost half a century of research on this topic has resulted in an enormous amount of data. In this essay, a general perspective to interpret all these data will be given. In classical endocrinology, neuropeptides were thought of as simple signalling molecules that each elicit one response. However, the fact that the total bioactive peptide signal is far from simple puts this view under pressure. Cells and tissues express many different (...) bioactive peptides and they are also able to respond to many different bioactive peptides, indicating that multiple receptors and signal transduction pathways are present in a single cell. Therefore, the authors suggest that the bioactive peptide signalling system should be regarded in the context of network and systems biology. Bioactive peptides can best be viewed as an extension of the protein interaction network that allows regulating and fine‐tuning the metabolism of the different cells and tissues in the body. The cell thus responds to the ‘peptidome’ instead of to a single peptide. The intracellular part of this signalling network consists of the various signalling transduction cascades. Recently, new systems biology approaches have emerged for the modelling of cell signalling. The network and systems biology approach is also able to shed new light on the evolution of intercellular signalling. (shrink)

NCG 4.0 is the latest update of the Network of Cancer Genes, a web-based repository of systems-level properties of cancer genes. In its current version, the database collects information on 537 known (i.e. experimentally supported) and 1463 candidate (i.e. inferred using statistical methods) cancer genes. Candidate cancer genes derive from the manual revision of 67 original publications describing the mutational screening of 3460 human exomes and genomes in 23 different cancer types. For all 2000 cancer genes, duplicability, evolutionary origin, expression, (...) functional annotation, interaction network with other human proteins and with microRNAs are reported. In addition to providing a substantial update of cancer-related information, NCG 4.0 also introduces two new features. The first is the annotation of possible false-positive cancer drivers, defined as candidate cancer genes inferred from large-scale screenings whose association with cancer is likely to be spurious. The second is the description of the systems-level properties of 64 human microRNAs that are causally involved in cancer progression (oncomiRs). Owing to the manual revision of all information, NCG 4.0 constitutes a complete and reliable resource on human coding and non-coding genes whose deregulation drives cancer onset and/or progression. NCG 4.0 can also be downloaded as a free application for Android smart phones. (shrink)

Chronic myeloid leukemia (CML) is a cancer of the hematopoietic system initiated by a single genetic mutation which results in the oncogenic fusion protein Bcr-Abl. Untreated, patients pass through different phases of the disease beginning with the rather asymptomatic chronic phase and ultimately culminating into blast crisis, an acute leukemia resembling phase with a very high mortality. Although many processes underlying the chronic phase are well understood, the exact mechanisms of disease progression to blast crisis are not yet revealed. (...) In this paper we develop a mathematical model of CML based on causal Bayesian networks in order to study possible disease progression mechanisms. Our results indicate that an increase of Bcr-Abl levels alone is not sufficient to explain the phenotype of blast crisis and that secondary changes such as additional mutations are necessary to explain disease progression and the poor therapy response of patients in blast crisis. (shrink)

The recent discovery and structure determination of a novel ubiquitin‐like dimerization domain in protein kinase D (PKD) has significant implications for its activation. PKD is a serine/threonine kinase activated by the lipid second messenger diacylglycerol (DAG). It is an essential and highly conserved protein that is implicated in plasma membrane directed trafficking processes from the trans‐Golgi network. However, many open questions surround its mechanism of activation, its localization, and its role in the biogenesis of cargo transport carriers. In (...) reviewing this field, the focus is primarily on the mechanisms that control the activation of PKD at precise locations in the cell. In light of the new structural findings, the understanding of the mechanisms underlying PKD activation is critically evaluated, with particular emphasis on the role of dimerization in PKD autophosphorylation, and the provenance and recognition of the DAG that activates PKD. (shrink)

Segregation of chromosomes during mitosis requires the interaction of dynamic microtubules with the kinetochore, a large protein structure established on the centromere region of sister chromatids. The core microtubule‐binding activity of the kinetochore resides in the KMN network, an outer kinetochore complex. As part of the KMN network, the Ndc80 complex, which is composed of Ndc80, Nuf2, Spc24, and Spc25, is able to bind directly to microtubules and has the ability to track with depolymerizing microtubules to produce chromosome movement. (...) The Ndc80 complex binds directly to microtubules through a calponin homology domain and an unstructured tail in the N terminus of the Ndc80 protein. A recent flurry of papers has highlighted the importance of an internal loop region in Ndc80 in establishing end‐on attachment to microtubules. Here I discuss these recent findings that suggest that the Ndc80 internal loop functions as a binding site for proteins required for kinetochore‐microtubule interactions. (shrink)

Our understanding of how evolution acts on biological networks remains patchy, as is our knowledge of how that action is best identified, modelled and understood. Starting with network structure and the evolution of protein–protein interaction networks, we briefly survey the ways in which network evolution is being addressed in the fields of systems biology, development and ecology. The approaches highlighted demonstrate a movement away from a focus on network topology towards a more integrated view, placing biological (...) properties centre‐stage. We argue that there remains great potential in a closer synergy between evolutionary biology and biological network analysis, although that may require the development of novel approaches and even different analogies for biological networks themselves. (shrink)

DNA–protein interactions are fundamental to many biological processes, including the regulation of gene expression. Determining the binding affinities of transcription factors (TFs) to different DNA sequences allows the quantitative modeling of transcriptional regulatory networks and has been a significant technical challenge in molecular biology for many years. A recent paper by Maerkl and Quake1 demonstrated the use of microfluidic technology for the analysis of DNA–protein interactions. An array of short DNA sequences was spotted onto a glass slide, (...) which was then covered with a microfluidic device allowing each spot to be within a chamber into which the flow of materials was controlled by valves. By trapping the DNA–protein complexes on the surface and measuring their concentrations microscopically, they could determine the binding affinity to a large number of DNA sequences that were varied systematically. They studied four TFs from the basic helix–loop–helix family of proteins, all of which bind to E‐box sites with the consensus CAnnTG (where “n” can be any base), and showed that variations in affinity for different sites allows each TF to regulate different genes. BioEssays 29:717–721, 2007. © 2007 Wiley Periodicals, Inc. (shrink)

All the conserved detailed results of evolution stored in DNA must be read, transcribed, and translated via an RNAmediated process. This is required for the development and growth of each individual cell. Thus, all known living organisms fundamentally depend on these RNA-mediated processes. In most cases, they are interconnected with other RNAs and their associated protein complexes and function in a strictly coordinated hierarchy of temporal and spatial steps (i.e., an RNA network). Clearly, all cellular life as we know (...) it could not function without these key agents of DNA replication, namely rRNA, tRNA, and mRNA. Thus, any definition of life that lacks RNA functions and their networks misses an essential requirement for RNA agents that inherently regulate and coordinate (communicate to) cells, tissues, organs, and organisms. The precellular evolution of RNAs occurred at the core of the emergence of cellular life and the question remained of how both precellular and cellular levels are interconnected historically and functionally. RNA-networks andRNA-communication can interconnect these levels.With the reemergence of virology in evolution, it became clear that communicating viruses and subviral infectious genetic parasites are bridging these two levels by invading, integrating, coadapting, exapting, and recombining constituent parts in host genomes for cellular requirements in gene regulation and coordination aims. Therefore, a 21st century understanding of life is of an inherently social process based on communicating RNA networks, in which viruses and cells continuously interact. (shrink)

How can our societies be stabilized in a crisis? Why do we enjoy and understand Shakespeare? Why are fruitflies uniform? How do omnivorous eating habits aid our survival? What makes the Mona Lisa's smile beautiful? How do women keep their social structures intact? -- Could there possibly be a single answer to all these questions? This book shows that the statement 'weak links stabilize complex systems' provides the key to understanding each of these intriguing puzzles, and many others too. The (...) author...uses weak (low affinity, low probability) interactions as a thread to introduce a vast variety of networks from proteins to economics and ecosystems. --From publisher description. (shrink)

Adaptors are proteins of multi‐modular structure without enzymatic activity. Their capacity to organise large, temporary protein complexes by linking proteins together in a regulated and selective fashion makes them of outstanding importance in the establishment and maintenance of specificity and efficiency in all known signal transduction pathways. This review focuses on the structural and functional characterisation of adaptors involved in tyrosine kinase (TK) signalling. TK‐linked adaptors can be distinguished by their domain composition and binding specificities. However, such structural classifications (...) have proven inadequate as indicators of functional roles. A better way to understand the logic of signalling networks might be to look at functional aspects of adaptor proteins such as signalling specificity, negative versus positive contribution to signal propagation, or their position in the signalling hierarchy. All of these functions are dynamic, suggesting that adaptors have important regulatory roles rather than acting only as stable linkers in signal transduction. BioEssays 28: 465–479, 2006. © 2006 Wiley Periodicals, Inc. (shrink)

Systems biology has provided new resources for discovering and reasoning about mechanisms. In addition to generating databases of large bodies of data, systems biologists have introduced platforms such as Cytoscape to represent protein–protein interactions, gene interactions, and other data in networks. Networks are inherently flat structures. One can identify clusters of highly connected nodes, but network representations do not represent these clusters as at a higher level than their constituents. Mechanisms, however, are hierarchically organized: they can (...) be decomposed into their parts and their activities can be decomposed into component operations. A potent bridge between flat networks and hierarchical mechanisms is provided by biological ontologies, both those curated by hand such as Gene Ontology and those extracted directly from databases such as Network Extracted Ontology. I examine several examples in which by applying ontologies to networks, systems biologists generate new hypotheses about mechanisms and characterize these novel strategies for developing mechanistic explanations. (shrink)

Through their transcript products genes regulate the rates at which an immense variety of transcripts and subsequent proteins occur. Understanding the mechanisms that determine which genes are expressed, and when they are expressed, is one of the keys to genetic manipulation for many purposes, including the development of new treatments for disease. Viewing each gene in a genome as a distinct variable that is either on or off, or more realistically as a continuous variable, the values of some of these (...) variables influence the values of others through the regulatory proteins they express, including, of course, the possibility that the rate of expression of a gene at one time may, in various circumstances, influence the rate of expression of that same gene at a later time. If we imagine an arrow drawn from each gene expression variable at a given time to a gene variable whose expression it influences a short while after, the result is a network, technically a directed acyclic graph. For example, the DAG in Figure 1 is a representation of a system in which the expression level of gene G1 at time 1 ) causes the expression level of G2, which in turn causes the expression level of G3. The arrows in Figure 1 which do not have a variable at their tails are “error terms” which represent all of the causes of a variable other than the ones explicitly represented in the DAG. The DAG describes more than associations—it describes causal connections among gene expression rates. A shock to a cell—by mutation, heating, chemical treatment, etc. may alter the DAG describing the relations among gene expressions, for example by activating a gene that was otherwise not expressed, producing a cascade of new expression effects. Although “knockout” experiments can reveal some of the underlying causal network of gene expression levels, unless guided by information from other sources, such experiments are limited in how much of the network structure they can reveal, due to the sheer number of possible combinations of experimental manipulations of genes necessary to reveal the complete causal network. Recent developments have made it possible to compare quantitatively the expression of tens of thousands of genes in cells from different sources in a single experiment, and to trace gene expression over time in thousands of genes simultaneously. cDNA microarrays are already producing extensive data, much of it available on the web. Thus there are calls for analytic software that can be applied to microarray and other data to help infer regulatory networks. In this paper we will review current techniques that are available for searching for the causal relations between variables, describe algorithmic and data gathering obstacles to applying these techniques to gene expression levels, and describe the prospects for overcoming these obstacles. (shrink)

The inositol phosphate metabolism network has been found to be much more complex than previously thought, as more and more inositol phosphates and their metabolizing enzymes have been discovered. Some of the inositol phosphates have been shown to have biological activities, but little is known about their signal transduction mechanisms except for that of inositol 1,4,5‐trisphosphate. The recent discovery, however, of a number of binding proteins for inositol high polyphosphate [inositol 1,3,4,5‐tetrakisphosphate (IP4), inositol 1,3,4,5,6‐pentakisphosphate, or inositol hexakisphosphate] enables us to (...) speculate on the physiological function of these compounds. In this article we focus on two major issues: (1) the roles of inositol high polyphosphates in vesicular trafficking, especially exocytosis, and (2) pleckstrin homology domaincontaining IP4 binding proteins involved in the Ras signaling pathway. (shrink)

Lysosomes are the site of degradation of obsolete intracellular material during autophagy and of extracellular macromolecules following endocytosis and phagocytosis. The membrane of lysosomes and late endosomes is enriched in highly glycosylated transmembrane proteins of largely unknown function. Significant progress has been made in recent years towards elucidating the pathways by which these lysosomal membrane proteins are delivered to late endosomes and lysosomes. While some lysosomal membrane proteins follow the constitutive secretory pathway and reach lysosomes indirectly via the cell surface (...) and endocytosis, others exit the trans‐Golgi network in clathrin‐coated vesicles for direct delivery to endosomes and lysosomes. Sorting from the Golgi or the plasma membrane into the endosomal system is mediated by signals encoded by the short cytosolic domain of these proteins. This review will discuss the role of lysosomal membrane proteins in the biogenesis of the late endosomal and lysosomal membranes, with particular emphasis on the structural features and molecular mechanisms underlying the intracellular trafficking of these proteins. (shrink)

Despite the recent progress in the description of the molecular mechanisms of proliferation and differentiation controls in vitro, the regulation of the homeostasis of normal stratified epithelia remains unclear in vivo. Computer simulation represents a powerful tool to investigate the complex field of cell proliferation regulation networks. It provides huge computation capabilities to test, in a dynamic in silico context, hypotheses about the many pathways and feedback loops involved in cell growth and proliferation controls.Our approach combines a model of (...) cell proliferation and a spatial representation of cells in 2D using the Voronoi graph. The cell proliferation model includes intracellular (cyclins, Cyclin Dependent Kinases - CDKs, Retinoblastoma protein - Rb, CDK inhibitors) and extracellular controls (growth and differentiation factors, integrins). The Voronoi graph associates a polygon with every cell and the set of these polygons defines the tissue architecture. Thus, the model provides a quantitative model of extracellular signals and cell motility as a function of the neighborhood during time dependent simulations. (shrink)

The interconversion of key regulatory proteins between phosphorylated and dephosphorylated forms is an extremely versatile mechanism for reversible altering their activities, and in mammalian cells may be almost as common as allosteric regulation. It is now evident that protein phosphorylation is the basis of a complex network of interlocking systems which allow a variety of hormones and other extracellular signals, acting through just a few second messengers to coordinate biochemical functions.

The complexity of intracellular molecular pathways can be simplified by the use of Network Biology that breaks down the intricacy of biological processes into components and interactions among them. In the paper we show that any complex interactome, that is, a biological network representing protein-protein, protein-DNA and DNA-RNA interactions, can be decomposed into a conjunction of logical theorems expressed in terms of Zsyntax, a formal language which allows representing biological pathways. This result, illustrated with the case study (...) of melanoma network, opens the possibility for a computable model of the cell expressed in a logical language and shows how a formal way of intending philosophy can be useful to cope with the complexity of the biological world. (shrink)

Intercellular communication is an essential process in all multicellular organisms. During this process, molecules secreted by one cell will bind to a receptor on the cognate cell leading to the subsequent uptake of the receptor‐ligand complex. Once inside, the cell then determines the fate of the receptor‐ligand complex and any other proteins that were endocytosed together. Approximately 80% of endocytosed material is recycled back to the plasma membrane either directly or indirectly via the Golgi apparatus and the remaining 20% is (...) delivered to the lysosome for degradation. Although most pathways have been identified, we still lack understanding on how specificity in sorting of recycling cargos into different pathways is achieved, and how the cell reaches high accuracy of these processes in the absence of clear sorting signals in the bulk of the client proteins. In this review, we will summarize our current understanding of the mechanism behind recycling cargo sorting and propose a model of differential affinities between cargo and cargo receptors/adaptors with regards to iterative sorting in endosomes. (shrink)

It was initially believed that G‐protein‐coupled receptors, such as metabotropic glutamate receptors, could simply be described as individual proteins that are associated with intracellular signal cascades via G‐proteins. This view is no longer tenable. Today we know that metabotropic glutamate receptors (mGluRs) can dimerize and bind to a variety of proteins in addition to trimeric G‐proteins. These newly identified protein interactions led to the discovery of new regulatory mechanisms that are independent of and sometimes synergistic with the classical (...) G‐protein‐coupled second messenger pathways. Notably, several of these mechanisms connect mGluR‐mediated signaling to other receptor classes, thereby creating a network of different receptor types and associated signal cascades. The intracellular C‐termini of mGluRs play a key role in the regulation of these networks, and various new protein interactions of these domains were described recently. Because mGluRs are involved in a variety of physiological and pathophysiological processes, some of the proteins interacting with this receptor class have potential as valuable pharmaceutical targets. This review will give a comprehensive overview of proteins interacting with mGluR C‐termini, highlight new evolving regulatory mechanisms for glutamatergic signal transduction and discuss possibilities for future drug development. BioEssays 29: 60–73, 2007. © 2006 Wiley Periodicals, Inc. (shrink)

The accurate annotation of an unknown protein sequence depends on extant data of template sequences. This could be empirical or sets of reference sequences, and provides an exhaustive pool of probable functions. Individual methods of predicting dominant function possess shortcomings such as varying degrees of inter-sequence redundancy, arbitrary domain inclusion thresholds, heterogeneous parameterization protocols, and ill-conditioned input channels. Here, I present a rigorous theoretical derivation of various steps of a generic algorithm that integrates and utilizes several statistical methods to (...) predict the dominant function in unknown protein sequences. The accompanying mathematical proofs, interval definitions, analysis, and numerical computations presented are meant to offer insights not only into the specificity and accuracy of predictions, but also provide details of the operatic mechanisms involved in the integration and its ensuing rigor. The algorithm uses numerically modified raw hidden markov model scores of well defined sets of training sequences and clusters them on the basis of known function. The results are then fed into an artificial neural network, the predictions of which can be refined using the available data. This pipeline is trained recursively and can be used to discern the dominant principal function, and thereby, annotate an unknown protein sequence. Whilst, the approach is complex, the specificity of the final predictions can benefit laboratory workers design their experiments with greater confidence. -/- . (shrink)

Members of the serine/arginine (SR)‐rich protein family of splicing factors play versatile roles in RNA processing steps and are often essential for normal development. Dynamic changes in RNA processing and turnover allow fast cellular adaptions to a changing microenvironment and thereby closely cooperate with transcription factor networks that establish cell identity within tissues. SR proteins play fundamental roles in the processing of pre‐mRNAs by regulating constitutive and alternative splicing. More recently, SR proteins have also been implicated in other (...) aspects of RNA metabolism such as mRNA stability, transport and translation. The‐ emerging noncanonical functions highlight the multifaceted functions of these SR proteins and identify them as important coordinators of gene expression programmes. Accordingly, most SR proteins are essential for normal cell function and their misregulation contributes to human diseases such as cancer. (shrink)

In Escherichia coli, the workhorse of molecular biology, a single operon is involved in the replication, transcription and translation of genetic information. This operon is controlled in a complex manner involving multiple cis‐acting regulatory sequences and trans‐acting regulatory proteins. It interacts with global regulatory networks by mechanisms which are presently being dissected.

In Escherichia coli, the workhorse of molecular biology, a single operon is involved in the replication, transcription and translation of genetic information. This operon is controlled in a complex manner involving multiple cis‐acting regulatory sequences and trans‐acting regulatory proteins. It interacts with global regulatory networks by mechanisms which are presently being dissected.