Single molecule and NMR measurements of protein dynamics increasingly uncover the complexity of binding scenarios. Here we describe an extended conformational selection model which embraces a repertoire of selection and adjustment processes. Induced fit can be viewed as a subset of this repertoire, whose contribution is affected by the bond-types stabilizing the interaction and the differences between the interacting partners. We argue that protein segments whose dynamics are distinct from the rest of the protein ('discrete breathers') can govern conformational transitions and allosteric propagation that accompany binding processes, and as such might be more sensitive to mutational events. Additionally, we highlight the dynamic complexity of binding scenarios as they relate to events such as aggregation and signalling, and the crowded cellular environment.
Single molecule and NMR measurements of protein dynamics increasingly uncover the complexity of binding scenarios. Here we describe an extended conformational selection model which embraces a repertoire of selection and adjustment processes. Induced fit can be viewed as a subset of this repertoire, whose contribution is affected by the bondtypes stabilizing the interaction and the differences between the interacting partners. We argue that protein segments whose dynamics are distinct from the rest of the protein ('discrete breathers') can govern conformational transitions and allosteric propagation that accompany binding processes, and as such may be more sensitive to mutational events. Additionally, we highlight the dynamic complexity of binding scenarios as they relate to events such as aggregation and signalling, and the crowded cellular environment. The induced fit and the original conformational selection modelsThe prevailing view of binding mechanisms has evolved from the early 'lock-and-key' hypothesis [1] to the now popular 'induced fit' model [2]. According to the induced fit scenario, the interaction between a protein and a rigid binding partner induces a conformational change in the protein. However, several systems follow the 'conformational selection' (or, with a different nomenclature, population selection, fluctuation fit, selected fit) paradigm, where among the conformations of the dynamically fluctuating protein the ligand selects the one, which is compatible with binding, and shifts the conformational ensemble towards this state. Selective binding to a single conformation in the ensemble was suggested by Straub as early as 1964 [3]; initial experimental evidence for the hypothesis came from Zavodszky et al. [4] in 1966. Over twenty five years later, in a landmark paper, Frauenfelder, Sligar and Wolynes [5] described the energy landscape of proteins, which in 1999 led to the generalized concept of 'conformational selection and population shift' [6,7]. The observed widespread occurrence of such conformational selection phenomena and their importance in functional scenarios is increasingly supported by X-ray and cryo-electron microscope images, kinetics studies, extensive single molecule fluorescence and in particular, NMR data showing a repertoire of conformational states of unliganded proteins reflecting in vivo occurrences, including conformations corresponding to the bound form [8][9][10].The duality of the induced fit and the original conformational selection models resembles the model pair of the Koshland-Nemethy-Filmer (KNF, [11]) and the Monod-Wyman-Changeux (MWC) models [12] which explain allosteric interactions. Both models describe the allosteric effect as a binding event at one site, which induces a conformational change affecting the activity at another site. However, the KNF-model views the conformational change as a consequence of allosteric binding, whereas the MWC-model describes the conformational change as an allosteric ligand-induced shift of the equilibrium of two, pre-existing...
BackgroundNetwork communities help the functional organization and evolution of complex networks. However, the development of a method, which is both fast and accurate, provides modular overlaps and partitions of a heterogeneous network, has proven to be rather difficult.Methodology/Principal FindingsHere we introduce the novel concept of ModuLand, an integrative method family determining overlapping network modules as hills of an influence function-based, centrality-type community landscape, and including several widely used modularization methods as special cases. As various adaptations of the method family, we developed several algorithms, which provide an efficient analysis of weighted and directed networks, and (1) determine pervasively overlapping modules with high resolution; (2) uncover a detailed hierarchical network structure allowing an efficient, zoom-in analysis of large networks; (3) allow the determination of key network nodes and (4) help to predict network dynamics.Conclusions/SignificanceThe concept opens a wide range of possibilities to develop new approaches and applications including network routing, classification, comparison and prediction.
The network paradigm is increasingly used to describe the topology and dynamics of complex systems. Here, we review the results of the topological analysis of protein structures as molecular networks describing their small-world character, and the role of hubs and central network elements in governing enzyme activity, allosteric regulation, protein motor function, signal transduction and protein stability. We summarize available data how central network elements are enriched in active centers and ligand binding sites directing the dynamics of the entire protein. We assess the feasibility of conformational and energy networks to simplify the vast complexity of rugged energy landscapes and to predict protein folding and dynamics. Finally, we suggest that modular analysis, novel centrality measures, hierarchical representation of networks and the analysis of network dynamics will soon lead to an expansion of this field.
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The complex integrity of the cells and its sudden, but often predictable changes can be described and understood by the topology and dynamism of cellular networks. All these networks undergo both local and global rearrangements during stress and development of diseases. Here, we illustrate this by showing the stress-induced structural rearrangement of the yeast protein-protein interaction network (interactome). In an unstressed state, the yeast interactome is highly compact, and the centrally organized modules have a large overlap. During stress, several original modules became more separated, and a number of novel modules also appear. A few basic functions such as theproteasome preserve their central position; however, several functions with high energy demand, such the cell-cycle regulation loose their original centrality during stress. A number of key stress-dependent protein complexes, such as the disaggregation-specific chaperone, Hsp104 gain centrality in the stressed yeast interactome. Molecular chaperones, heat shock, or stress proteins became established as key elements in our molecular understanding of the cellular stress response. Chaperones form complex interaction networks (the chaperome) with each other and their partners. Here, we show that the human chaperome recovers the segregation of protein synthesis-coupled and stress-related chaperones observed in yeast recently. Examination of yeast and human interactomes shows that chaperones 1) are intermodular integrators of protein-protein interaction networks, which 2) often bridge hubs and 3) are favorite candidates for extensive phosphorylation. Moreover, chaperones 4) become more central in the organization of the isolated modules of the stressed yeast protein-protein interaction network, which highlights their importance in the decoupling and recoupling of network modules during and after stress. Chaperone-mediated evolvability of cellular networks may play a key role in cellular adaptation during stress and various polygenic and chronic diseases, such as cancer, diabetes or neurodegeneration.
In the past few years, network-based tools have become increasingly important in the identification of novel molecular targets for drug development. Systems-based approaches to predict signal transduction-related drug targets have developed into an especially promising field. Here, we summarize our studies, which indicate that modular bridges and overlaps of protein-protein interaction and signaling networks may be of key importance in future drug design. Intermodular nodes are very efficient in mediating the transmission of perturbations between signaling modules and are important in network cooperation. The analysis of stress-induced rearrangements of the yeast interactome by the ModuLand modularization algorithm indicated that components of modular overlap are key players in cellular adaptation to stress. Signaling crosstalk was much more pronounced in humans than in Caenorhabditis elegans or Drosophila melanogaster in the SignaLink (http://www.SignaLink.org) database, a uniformly curated database of eight major signaling pathways. We also showed that signaling proteins that participate in multiple pathways included multiple established drug targets and drug target candidates. Lastly, we caution that the pervasive overlap of cellular network modules implies that wider use of multitarget drugs to partially inhibit multiple individual proteins will be necessary to modify specific cellular functions, because targeting single proteins for complete disruption usually affects multiple cellular functions with little specificity for a particular process. Tools for analyzing network topology and especially network dynamics have great potential to identify alternative sets of targets for developing multitarget drugs.
BackgroundUncovering novel components of signal transduction pathways and their interactions within species is a central task in current biological research. Orthology alignment and functional genomics approaches allow the effective identification of signaling proteins by cross-species data integration. Recently, functional annotation of orthologs was transferred across organisms to predict novel roles for proteins. Despite the wide use of these methods, annotation of complete signaling pathways has not yet been transferred systematically between species.Principal FindingsHere we introduce the concept of ‘signalog’ to describe potential novel signaling function of a protein on the basis of the known signaling role(s) of its ortholog(s). To identify signalogs on genomic scale, we systematically transferred signaling pathway annotations among three animal species, the nematode Caenorhabditis elegans, the fruit fly Drosophila melanogaster, and humans. Using orthology data from InParanoid and signaling pathway information from the SignaLink database, we predict 88 worm, 92 fly, and 73 human novel signaling components. Furthermore, we developed an on-line tool and an interactive orthology network viewer to allow users to predict and visualize components of orthologous pathways. We verified the novelty of the predicted signalogs by literature search and comparison to known pathway annotations. In C. elegans, 6 out of the predicted novel Notch pathway members were validated experimentally. Our approach predicts signaling roles for 19 human orthodisease proteins and 5 known drug targets, and suggests 14 novel drug target candidates.ConclusionsOrthology-based pathway membership prediction between species enables the identification of novel signaling pathway components that we referred to as signalogs. Signalogs can be used to build a comprehensive signaling network in a given species. Such networks may increase the biomedical utilization of C. elegans and D. melanogaster. In humans, signalogs may identify novel drug targets and new signaling mechanisms for approved drugs.
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