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)

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)

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)

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)

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)

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)

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)

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)

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)

This paper deals with the problem of reconstruction of the intergenic interaction graph from the raw data of genetic co-expression coming with new technologies of bio-arrays (DMA-arrays, protein-arrays, etc.). These new imaging devices in general only give information about the asymptotical part (fixed configurations of co-expression or limit cycles of such configurations) of the dynamical evolution of the regulatory networks (genetic and/or proteic) underlying the functioning of living systems. Extracting the casual structure and interaction coefficients of (...) a gene interaction network from the observed configurations is a complex problem. But if all the fixed configurations are supposedly observed and if they are factorizable into two or more subsets of values, then the interaction graph possesses as many connected components as the number of factors and the solution is obtained in polynomial time. This new result allows us for example to partly solve the topology of the genetic regulatory network ruling the flowering in Arabidopsis thaliana. (shrink)

Niels Kaj Jerne has proposed the “immune network theory” of interactions among anti‐idiotypic antibodies, able to interfere with humoral responses to certain antigens. After the occurrence of the primary generation of antibodies, against an antigenic epitope, idiotypes of these antibodies induce anti‐idiotypic antibodies that modulate the intensity of the first response, and so on. Adverse effects following SARS‐COV‐2 COVID‐19 vaccines are occasionally similar to the symptoms of COVID‐19 infection. Rare events linked to SARS‐CoV‐2 vaccines also resemble some rarely reported COVID‐19 (...) complications. Safety data from product information by European Medicines Agency suggest that spectra do overlap for four main vaccines. The proposition is that vaccine events and COVID‐19 complications are related to anti‐idiotypic antibodies whose spatial shape can lead to interactions with ACE2 molecules, in individuals with a prolonged Spike protein synthesis. The vaccines target cells by their affinity to the vaccine vector, or to engulf lipid nanoparticles. Anti‐idiotypic antibodies shaped similarly to the Spike protein possibly interact with ACE2 molecules and cause diverse signs and symptoms. (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)

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)

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)

Graphical AbstractDomains can spread among proteins in a process called domain shuffling and this has been identified as one of the major mechanisms leading to the formation of new proteins throughout evolution. This process has an impact on the topology of protein-protein interaction networks as it may create new hubs and also increase interconnectivity.

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)

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)

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)

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)

Interactions among membrane proteins regulate numerous cellular processes, including cell growth, cell differentiation and apoptosis. We need to understand which proteins interact, where they interact and to which extent they interact. This article describes a set of novel approaches to measure, on the surface of living cells, the number of clusters of proteins, the number of proteins per cluster, the number of clusters or membrane domains that contain pairs of interacting proteins and the fraction of one protein species that (...) interacts with another protein within these domains. These data can then be interpreted in terms of the function of the protein‐protein interactions. BioEssays 26:196–203, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

COVID-19 often manifests with different outcomes in different patients, highlighting the complexity of the host-pathogen interactions involved in manifestations of the disease at the molecular and cellular levels. In this paper, we propose a set of postulates and a framework for systematically understanding complex molecular host-pathogen interaction networks. Specifically, we first propose four host-pathogen interaction (HPI) postulates as the basis for understanding molecular and cellular host-pathogen interactions and their relations to disease outcomes. These four postulates cover the (...) evolutionary dispositions involved in HPIs, the dynamic nature of HPI outcomes, roles that HPI components may occupy leading to such outcomes, and HPI checkpoints that are critical for specific disease outcomes. Based on these postulates, an HPI Postulate and Ontology (HPIPO) framework is proposed to apply interoperable ontologies to systematically model and represent various granular details and knowledge within the scope of the HPI postulates, in a way that will support AI-ready data standardization, sharing, integration, and analysis. As a demonstration, the HPI postulates and the HPIPO framework were applied to study COVID-19 with the Coronavirus Infectious Disease Ontology (CIDO), leading to a novel approach to rational design of drug/vaccine cocktails aimed at interrupting processes occurring at critical host-coronavirus interaction checkpoints. Furthermore, the host-coronavirus protein-protein interactions (PPIs) relevant to COVID-19 were predicted and evaluated based on prior knowledge of curated PPIs and domain-domain interactions, and how such studies can be further explored with the HPI postulates and the HPIPO framework is discussed. (shrink)

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)

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.

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)

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)

Transcription factor (TF) signaling regulates gene transcription and requires a complex network of proteins. This network includes co‐activators, co‐repressors, multiple TFs, histone‐modifying complexes, and the basal transcription machinery. It has been widely appreciated that pioneer factors, such as FoxA1 and GATA1, play an important role in opening closed chromatin regions, thereby allowing binding of a secondary factor. In this review we will focus on a newly proposed model wherein multiple TFs, such as steroid receptors (SRs), can function in a pioneering (...) role. This model, termed dynamic assisted loading, integrates data from widely divergent methodologies, including genome wide ChIP‐Seq, digital genomic footprinting, DHS‐Seq, live cell protein dynamics, and biochemical studies of ATP‐dependent remodeling complexes, to present a real time view of TF chromatin interactions. Under this view, many TFs can act as initiating factors for chromatin landscape programming. Furthermore, enhancer and promoter states are more accurately described as energy‐dependent, non‐equilibrium steady states. (shrink)

Large protein assemblies are usually the effectors of major cellular processes. The intricate cell homeostasis network is divided into numerous interconnected pathways, each controlled by a set of protein machines. One of these master regulators is the CCR4‐NOT complex, which ultimately controls protein expression levels. This multisubunit complex assembles around a scaffold platform, which enables a wide variety of well‐studied functions from mRNA synthesis to transcript decay, as well as other tasks still being identified. Solving the structure (...) of the entire CCR4‐NOT complex will help to define the distribution of its functions. The recently published three‐dimensional reconstruction of the complex, in combination with the known crystal structures of some of the components, has begun to address this. Methodological improvements in structural biology, especially in cryoelectron microscopy, encourage further structural and protein‐protein interaction studies, which will advance our comprehension of the gene expression machinery. (shrink)

The discovery and engineering of novel fluorescent proteins (FPs) from diverse organisms is yielding fluorophores with exceptional characteristics for live‐cell imaging. In particular, the development of FPs for fluorescence (or Förster) resonance energy transfer (FRET) microscopy is providing important tools for monitoring dynamic protein interactions inside living cells. The increased interest in FRET microscopy has driven the development of many different methods to measure FRET. However, the interpretation of FRET measurements is complicated by several factors including the high fluorescence (...) background, the potential for photoconversion artifacts and the relatively low dynamic range afforded by this technique. Here, we describe the advantages and disadvantages of four methods commonly used in FRET microscopy. We then discuss the selection of FPs for the different FRET methods, identifying the most useful FP candidates for FRET microscopy. The recent success in expanding the FP color palette offers the opportunity to explore new FRET pairs. (shrink)

Much contemporary nanotoxicology, nanotherapeutic and nanoregulatory research has been characterised by a focus on investigating how delivery of engineered nanoparticles (ENPs) to cells is dictated primarily by components of the ENP surface. An alternative model, some implications of which are discussed here, begins with fundamental physicochemical research into the interaction of a dynamic nanoparticle-protein corona (NPC) with biological systems. The proposed new model also requires, however, that any such fresh NPC physicochemical research approach should involve integration and targeted (...) collaboration from the earliest stages with nanotoxicology, nanotherapeutics and nanoregulatory expertise. The justification for this integrated approach, we argue, relates not just to efficiency and promotion of innovation, but to an acknowledgement that public-funded basic physicochemical research in particular should now be accepted to incorporate strong higher order public goods elements from its inception, not merely after product development at the technology transfer stage. Issues, in other words, such as university research co-operation, commercialization and intellectual property (IP) protection, safety and cost-effectiveness regulatory assessment, as well as technology transfer should not be viewed as second tier considerations even in a ‘blue sky’ NPC basic research agenda. (shrink)

The tetratricopeptide repeat (TPR) motif is a protein-protein interaction module found in multiple copies in a number of functionally different proteins that facilitates specific interactions with a partner protein(s). Three-dimensional structural data have shown that a TPR motif contains two antiparallel α-helices such that tandem arrays of TPR motifs generate a right-handed helical structure with an amphipathic channel that might accommodate the complementary region of a target protein. Most TPR-containing proteins are associated with multiprotein complexes, (...) and there is extensive evidence indicating that TPR motifs are important to the functioning of chaperone, cell-cycle, transcription, and protein transport complexes. The TPR motif may represent an ancient protein-protein interaction module that has been recruited by different proteins and adapted for specific functions. BioEssays 1999;21:932–939. © 1999 John Wiley & Sons, Inc. (shrink)

The tetratricopeptide repeat (TPR) motif is a protein-protein interaction module found in multiple copies in a number of functionally different proteins that facilitates specific interactions with a partner protein(s). Three-dimensional structural data have shown that a TPR motif contains two antiparallel α-helices such that tandem arrays of TPR motifs generate a right-handed helical structure with an amphipathic channel that might accommodate the complementary region of a target protein. Most TPR-containing proteins are associated with multiprotein complexes, (...) and there is extensive evidence indicating that TPR motifs are important to the functioning of chaperone, cell-cycle, transcription, and protein transport complexes. The TPR motif may represent an ancient protein-protein interaction module that has been recruited by different proteins and adapted for specific functions. BioEssays 1999;21:932–939. © 1999 John Wiley & Sons, Inc. (shrink)

Broad‐complex, Tramtrack, and Bric‐à‐brac/poxvirus and zinc finger (BTB/POZ) is a conserved domain found in many eukaryotic proteins with diverse cellular functions. Recent studies revealed its importance in multiple developmental processes as well as in the onset and progression of oncological diseases. Most BTB domains can form multimers and selectively interact with non‐BTB proteins. Structural studies of BTB domains delineated the presence of different interfaces involved in various interactions mediated by BTBs and provided a basis for the specific inhibition of distinct (...) protein‐interaction interfaces. BTB domains originated early in eukaryotic evolution and progressively adapted their structural elements to perform distinct functions. In this review, we summarize and discuss the structural principles of protein‐protein interactions mediated by BTB domains based on the recently published structural data and advances in protein modeling. We propose an update to the structure‐based classification of BTB domain families and discuss their evolutionary interconnections. (shrink)

Metazoan genomes contain thousands of protein‐coding and non‐coding RNA genes, most of which are differentially expressed, i.e., at different locations, at different times during development, or in response to environmental signals. Differential gene expression is achieved through complex regulatory networks that are controlled in part by two types of trans‐regulators: transcription factors (TFs) and microRNAs (miRNAs). TFs bind to cis‐regulatory DNA elements that are often located in or near their target genes, while miRNAs hybridize to cis‐regulatory RNA elements (...) mostly located in the 3′ untranslated region of their target mRNAs. Here, we describe how these trans‐regulators interact with each other in the context of gene regulatory networks to coordinate gene expression at the genome‐scale level, and discuss future challenges of integrating these networks with other types of functional networks. (shrink)

We propose a new hybrid data mining method for predicting protein-protein interactions combining Likelihood-Ratio with rule induction algorithms. In essence, the new method consists of using a rule induction algorithm to discover rules representing partitions of the data, and then the discovered rules are interpreted as “bins” which are used to compute likelihood ratios. This new method is applied to the prediction of protein-protein interactions in the Saccharomyces Cerevisiae genome, using predictive genomic features in an integrated (...) scheme. The results show that the new hybrid method outperforms a pure likelihood ratio based approach. (shrink)

The glucocorticoid receptor belongs to an important class of transcription factors that alter the expression of target genes in response to a specific hormone signal. The glucocorticoid receptor can function at least at three levels: (1) recruitment of the general transcription machinery; (2) modulation of transcription factor action, independent of DNA binding, through direct protein‐protein interactions; and (3) modulation of chromatin structure to allow the assembly of other gene regulatory proteins and/or the general transcription machinery on the DNA. (...) This review will focus on the multifaceted nature of protein‐protein interactions involving the glucocorticoid receptor and basal transcription factors, coactivators and other transcription factors, occurring at these different levels of regulation. (shrink)

Although interactions of proteins with glycosaminoglycans (GAGs), such as heparin and heparan sulphate, are of great biological importance, structural requirements for protein‐GAG binding have not been well‐characterised. Ionic interactions are important in promoting protein‐GAG binding. Polyelectrolyte theory suggests that much of the free energy of binding comes from entropically favourable release of cations from GAG chains. Despite their identical charges, arginine residues bind more tightly to GAGs than lysine residues. The spacing of these residues may determine protein‐GAG (...) affinity and specificity. Consensus sequences such as XBBBXXBX, XBBXBX and a critical 20 Å spacing of basic residues are found in some protein sites that bind GAG. A new consensus sequence TXXBXXTBXXXTBB is described, where turns bring basic interacting amino acid residues into proximity. Clearly, protein‐GAG interactions play a prominent role in cell‐cell interaction and cell growth. Pathogens including virus particles might target GAG‐binding sites in envelope proteins leading to infection. BioEssays 20:156–167, 1998. © 1998 John Wiley & Sons, Inc. (shrink)

Constructive Neutral Evolution is an evolutionary mechanism that can explain much molecular inter-dependence and organismal complexity without assuming positive selection favoring such dependency or complexity, either directly or as a byproduct of adaptation. It differs from but complements other non-selective explanations for complexity, such as genetic drift and the Zero Force Evolutionary Law, by being ratchet-like in character. With CNE, purifying selection maintains dependencies or complexities that were neutrally evolved. Preliminary treatments use it to explain specific genetic and molecular structures (...) or processes, such as retained gene duplications, the spliceosome, and RNA editing. Here we aim to expand the scope of such explanation beyond the molecular level, integrating CNE with Multi-Level Selection theory, and arguing that several popular higher-level selection scenarios are in fact instances of CNE. Suitably contextualized, CNE occurs at any level in the biological hierarchy at which natural selection as normally construed occurs. As examples, we focus on modularity in protein–protein interaction networks or “interactomes,” the origin of eukaryotic cells and the evolution of co-dependence in microbial communities—a variant of the “Black Queen Hypothesis” which we call the “Gray Queen Hypothesis”. (shrink)

The BTB domain is a protein–protein interaction motif that is found throughout eukaryotes. It determines a unique tri‐dimensional fold with a large interaction surface. The exposed residues are highly variable and can permit dimerization and oligomerization, as well as interaction with a number of other proteins. BTB‐containing proteins are numerous and control cellular processes that range from actin dynamics to cell‐cycle regulation. Here, we review findings in the field of transcriptional regulation to illustrate how the (...) high variability of the BTB has allowed related transcription factors to evolve different functional abilities. We then report how recent work has showed that, in spite of their high sequence divergence and apparently unrelated functions, many BTB‐containing proteins have at least one shared role: the recruitment of degradation targets to E3 ubiquitin ligase complexes. Taken together, these findings illustrate diverse and convergent functions of a versatile protein–protein interaction domain. BioEssays 28: 1194–1202, 2006. © 2006 Wiley Periodicals, Inc. (shrink)

Because a large number of molecular mechanisms involved in gene regulation have been described during the last decades, it is now becoming possible to address questions about the global structure of gene regulatory networks, at least in the case of some of the best-characterized organisms.This paper presents a global characterization of the transcriptional regulation in Escherichiacoli on the basis of the current data. The connectivity of the corresponding network was evaluated by analyzing the distribution of the number of genes (...) regulated by a given regulatory protein, and the distribution of the number of regulatory genes regulating a given regulated gene. The mean connectivity found (between 2 and 3) shows a rather loosely interconnected structure. Special emphasis is given to circular sequences of interactions (“circuits”) because of their critical dynamical properties. Only one-element circuits were found, in which negative autoregulation is the dominant architecture. These global properties are discussed in light of several pertinent theoretical approaches, as well as in terms of physiological and evolutionary considerations. BioEssays 20:433–440, 1998. © 1998 John Wiley & Sons Inc. (shrink)

Because a large number of molecular mechanisms involved in gene regulation have been described during the last decades, it is now becoming possible to address questions about the global structure of gene regulatory networks, at least in the case of some of the best-characterized organisms.This paper presents a global characterization of the transcriptional regulation in Escherichiacoli on the basis of the current data. The connectivity of the corresponding network was evaluated by analyzing the distribution of the number of genes (...) regulated by a given regulatory protein, and the distribution of the number of regulatory genes regulating a given regulated gene. The mean connectivity found (between 2 and 3) shows a rather loosely interconnected structure. Special emphasis is given to circular sequences of interactions (“circuits”) because of their critical dynamical properties. Only one-element circuits were found, in which negative autoregulation is the dominant architecture. These global properties are discussed in light of several pertinent theoretical approaches, as well as in terms of physiological and evolutionary considerations. BioEssays 20:433–440, 1998. © 1998 John Wiley & Sons Inc. (shrink)

Because a large number of molecular mechanisms involved in gene regulation have been described during the last decades, it is now becoming possible to address questions about the global structure of gene regulatory networks, at least in the case of some of the best-characterized organisms.This paper presents a global characterization of the transcriptional regulation in Escherichiacoli on the basis of the current data. The connectivity of the corresponding network was evaluated by analyzing the distribution of the number of genes (...) regulated by a given regulatory protein, and the distribution of the number of regulatory genes regulating a given regulated gene. The mean connectivity found (between 2 and 3) shows a rather loosely interconnected structure. Special emphasis is given to circular sequences of interactions (“circuits”) because of their critical dynamical properties. Only one-element circuits were found, in which negative autoregulation is the dominant architecture. These global properties are discussed in light of several pertinent theoretical approaches, as well as in terms of physiological and evolutionary considerations. BioEssays 20:433–440, 1998. © 1998 John Wiley & Sons Inc. (shrink)

Wnt proteins can activate different intracellular signaling cascades in various organisms by interacting with receptors of the Frizzled family. The first identified Wnt signaling pathway, the Wnt/β‐catenin pathway, has been studied in much detail and is highly conserved among species. As to non‐canonical Wnt pathways, the current situation is more nebulous partly because the intracellular mediators of this pathway are not yet fully understood and, in some cases, even identified. However, there are increasing data that prove the existence of non‐canonical (...) Wnt signaling and demonstrate its involvement in different developmental processes. In vertebrates, Wnt‐11 and Wnt‐5A can activate the Wnt/JNK pathway, which resembles the planar cell polarity pathway in Drosophila. The Wnt/Ca2+‐pathway has only been described in Xenopus and zebrafish so far and it is unclear whether it also exists in other organisms. Two recent papers provide us with new insight into non‐canonical Wnt signaling by (1) presenting a new intracellular mediator of non‐canonical signaling in Xenopus1 and (2) implicating the existence of an additional non‐canonical Wnt signaling pathway in flies.2 BioEssays 24:881–884, 2002. © 2002 Wiley Periodicals, Inc. (shrink)

Insulators play a central role in subdividing the chromosome into a series of discrete topologically independent domains and in ensuring that enhancers and silencers contact their appropriate target genes. In this review we first discuss the general characteristics of insulator elements and their associated protein factors. A growing collection of insulator proteins have been identified including a family of proteins whose expression is developmentally regulated. We next consider several unexpected discoveries that require us to completely rethink how insulators function (...) (and how they can best be assayed). These discoveries also require a reevaluation of how insulators might restrict or orchestrate (by preventing or promoting) interactions between regulatory elements and their target genes. We conclude by connecting these new insights into the mechanisms of insulator action to dynamic changes in the three‐dimensional topology of the chromatin fiber and the generation of specific patterns of gene activity during development and differentiation. (shrink)

Regulation of microtubule (MT) dynamics is essential for many cellular processes, but the machinery that controls MT dynamics remains poorly understood. MT plus‐end tracking proteins (+TIPs) are a set of MT‐associated proteins that dynamically track growing MT ends and are uniquely positioned to govern MT dynamics. +TIPs associate with each other in a complex array of inter‐ and intra‐molecular interactions known as the “+TIP network.” Why do so many +TIPs bind to other +TIPs? Typical answers include the ideas that these (...) interactions localize proteins where they are needed, deliver proteins to the cortex, and/or create regulatory pathways. We propose an additional and more mechanistic hypothesis: that +TIPs bind each other to create a superstructure that promotes MT assembly by constraining the structural fluctuations of the MT tip, thus acting as a polymerization chaperone. (shrink)

Constructive Neutral Evolution theory provides selectively neutral explanations of the origin and maintenance of biological complexity. This essay provides an analysis of CNE as an explanatory strategy defined by a tripartite set of conditions, and shows how this applies to cases of the evolution of complexity at higher-levels of the biological hierarchy. CNE was initially deployed to help explain a variety of complex molecular structures and processes, including spliceosomal splicing, trypansomal pan-editing, scrambled genes in ciliates, duplicate gene retention and fungal (...) ATP synthetase structure. CNE has also been generalized to apply to phenomena at the cellular level, including protein-protein interaction network modularity, obligate microbial symbioses, eukaryogenesis and microbial unculturability. This essay further extends CNE to cases of complexity at levels of organization higher than the molecular and cellular. These are multicellular phenotypic complexity, multicellular ecological complexity and, some cases of cultural complexity. (shrink)