Network Archaeology: Uncovering Ancient Networks from Present-day Interactions

Often questions arise about old or extinct networks. What proteins interacted in a long-extinct ancestor species of yeast? Who were the central players in the Last.fm social network 3 years ago? Our ability to answer such questions has been limited by the unavailability of past versions of networks. To overcome these limitations, we propose several algorithms for reconstructing a network's history of growth given only the network as it exists today and a generative model by which the network is believed to have evolved. Our likelihood-based method finds a probable previous state of the network by reversing the forward growth model. This approach retains node identities so that the history of individual nodes can be tracked. We apply these algorithms to uncover older, non-extant biological and social networks believed to have grown via several models, including duplication-mutation with complementarity, forest fire, and preferential attachment. Through experiments on both synthetic and real-world data, we find that our algorithms can estimate node arrival times, identify anchor nodes from which new nodes copy links, and can reveal significant features of networks that have long since disappeared.Comment: 16 pages, 10 figure

Turning the Table: Plants Consume Microbes as a Source of Nutrients

Interactions between plants and microbes in soil, the final frontier of ecology, determine the availability of nutrients to plants and thereby primary production of terrestrial ecosystems. Nutrient cycling in soils is considered a battle between autotrophs and heterotrophs in which the latter usually outcompete the former, although recent studies have questioned the unconditional reign of microbes on nutrient cycles and the plants' dependence on microbes for breakdown of organic matter. Here we present evidence indicative of a more active role of plants in nutrient cycling than currently considered. Using fluorescent-labeled non-pathogenic and non-symbiotic strains of a bacterium and a fungus (Escherichia coli and Saccharomyces cerevisiae, respectively), we demonstrate that microbes enter root cells and are subsequently digested to release nitrogen that is used in shoots. Extensive modifications of root cell walls, as substantiated by cell wall outgrowth and induction of genes encoding cell wall synthesizing, loosening and degrading enzymes, may facilitate the uptake of microbes into root cells. Our study provides further evidence that the autotrophy of plants has a heterotrophic constituent which could explain the presence of root-inhabiting microbes of unknown ecological function. Our discovery has implications for soil ecology and applications including future sustainable agriculture with efficient nutrient cycles

Phosphorylation State-Dependent Interactions of Hepadnavirus Core Protein with Host Factors

Dynamic phosphorylation and dephosphorylation of the hepadnavirus core protein C-terminal domain (CTD) are required for multiple steps of the viral life cycle. It remains unknown how the CTD phosphorylation state may modulate core protein functions but phosphorylation state-dependent viral or host interactions may play a role. In an attempt to identify host factors that may interact differentially with the core protein depending on its CTD phosphorylation state, pulldown assays were performed using the CTD of the duck hepatitis B virus (DHBV) and human hepatitis B virus (HBV) core protein, either with wild type (WT) sequences or with alanine or aspartic acid substitutions at the phosphorylation sites. Two host proteins, B23 and I2PP2A, were found to interact preferentially with the alanine-substituted CTD. Furthermore, the WT CTD became competent to interact with the host proteins upon dephosphorylation. Intriguingly, the binding site on the DHBV CTD for both B23 and I2PP2A was mapped to a region upstream of the phosphorylation sites even though B23 or I2PP2A binding to this site was clearly modulated by the phosphorylation state of the downstream and non-overlapping sequences. Together, these results demonstrate a novel mode of phosphorylation-regulated protein-protein interaction and provide new insights into virus-host interactions

A Comprehensive Resource of Interacting Protein Regions for Refining Human Transcription Factor Networks

Large-scale data sets of protein-protein interactions (PPIs) are a valuable resource for mapping and analysis of the topological and dynamic features of interactome networks. The currently available large-scale PPI data sets only contain information on interaction partners. The data presented in this study also include the sequences involved in the interactions (i.e., the interacting regions, IRs) suggested to correspond to functional and structural domains. Here we present the first large-scale IR data set obtained using mRNA display for 50 human transcription factors (TFs), including 12 transcription-related proteins. The core data set (966 IRs; 943 PPIs) displays a verification rate of 70%. Analysis of the IR data set revealed the existence of IRs that interact with multiple partners. Furthermore, these IRs were preferentially associated with intrinsic disorder. This finding supports the hypothesis that intrinsically disordered regions play a major role in the dynamics and diversity of TF networks through their ability to structurally adapt to and bind with multiple partners. Accordingly, this domain-based interaction resource represents an important step in refining protein interactions and networks at the domain level and in associating network analysis with biological structure and function

Conserved and variable correlated mutations in the plant MADS protein network

<p>Abstract</p> <p>Background</p> <p>Plant MADS domain proteins are involved in a variety of developmental processes for which their ability to form various interactions is a key requisite. However, not much is known about the structure of these proteins or their complexes, whereas such knowledge would be valuable for a better understanding of their function. Here, we analyze those proteins and the complexes they form using a correlated mutation approach in combination with available structural, bioinformatics and experimental data.</p> <p>Results</p> <p>Correlated mutations are affected by several types of noise, which is difficult to disentangle from the real signal. In our analysis of the MADS domain proteins, we apply for the first time a correlated mutation analysis to a family of interacting proteins. This provides a unique way to investigate the amount of signal that is present in correlated mutations because it allows direct comparison of mutations in various family members and assessing their conservation. We show that correlated mutations in general are conserved within the various family members, and if not, the variability at the respective positions is less in the proteins in which the correlated mutation does not occur. Also, intermolecular correlated mutation signals for interacting pairs of proteins display clear overlap with other bioinformatics data, which is not the case for non-interacting protein pairs, an observation which validates the intermolecular correlated mutations. Having validated the correlated mutation results, we apply them to infer the structural organization of the MADS domain proteins.</p> <p>Conclusion</p> <p>Our analysis enables understanding of the structural organization of the MADS domain proteins, including support for predicted helices based on correlated mutation patterns, and evidence for a specific interaction site in those proteins.</p

Multiple SNARE interactions of an SM protein: Sed5p/Sly1p binding is dispensable for transport

Sec1/Munc18 (SM) proteins are central to intracellular transport and neurotransmitter release but their exact role is still elusive. Several SM proteins, like the neuronal N-Sec1 and the yeast Sly1 protein, bind their cognate t-SNAREs with high affinity. This has been thought to be critical for their function. Here, we show that various mutant forms of Sly1p and the Golgi-localized syntaxin Sed5p, which abolish their high-affinity interaction, are fully functional in vivo, indicating that the tight interaction of the two molecules per se is not relevant for proper function. Mutant Sly1p unable to bind Sed5p is excluded from core SNARE complexes, also demonstrating that Sly1p function is not directly coupled to assembled SNARE complexes thought to execute membrane fusion. We also find that wild-type Sly1p and mutant Sly1p unable to bind Sed5p directly interact with selected ER-to-Golgi and intra-Golgi nonsyntaxin SNAREs. The newly identified, direct interactions of the SM protein with nonsytaxin SNAREs might provide a molecular mechanism by which SNAREs can be activated to engage in pairing and assemble into fusogenic SNARE complexes