Symbiosis: Receptive to infection
Symbiosis: Receptive to infection
Nature 523, 7560 (2015). doi:10.1038/nature14632
Authors: Sharon R. Long
EPR3, a plant protein, is found to act as a probable receptor for exopolysaccharide molecules that surround the plant's symbiotic bacteria. The advance sheds light on how recognition is governed in symbiotic relationships. See Article p.308
Receptor-mediated exopolysaccharide perception controls bacterial infection
Nature 523, 7560 (2015). doi:10.1038/nature14611
Authors: Y. Kawaharada, S. Kelly, M. Wibroe Nielsen, C. T. Hjuler, K. Gysel, A. Muszyński, R. W. Carlson, M. B. Thygesen, N. Sandal, M. H. Asmussen, M. Vinther, S. U. Andersen, L. Krusell, S. Thirup, K. J. Jensen, C. W. Ronson, M. Blaise, S. Radutoiu & J. Stougaard
Surface polysaccharides are important for bacterial interactions with multicellular organisms, and some are virulence factors in pathogens. In the legume–rhizobium symbiosis, bacterial exopolysaccharides (EPS) are essential for the development of infected root nodules. We have identified a gene in Lotus japonicus, Epr3, encoding
Progesterone receptor modulates ERα action in breast cancer
Nature 523, 7560 (2015). doi:10.1038/nature14583
Authors: Hisham Mohammed, I. Alasdair Russell, Rory Stark, Oscar M. Rueda, Theresa E. Hickey, Gerard A. Tarulli, Aurelien A. A. Serandour, Stephen N. Birrell, Alejandra Bruna, Amel Saadi, Suraj Menon, James Hadfield, Michelle Pugh, Ganesh V. Raj, Gordon D. Brown, Clive D’Santos, Jessica L. L. Robinson, Grace Silva, Rosalind Launchbury, Charles M. Perou, John Stingl, Carlos Caldas, Wayne D. Tilley & Jason S. Carroll
Progesterone receptor (PR) expression is used as a biomarker of oestrogen receptor-α (ERα) function and breast cancer prognosis. Here we show that PR is not merely an ERα-induced gene target, but is also an ERα-associated protein that modulates its behaviour. In the presence of agonist
Intersecting transcription networks constrain gene regulatory evolution
Nature 523, 7560 (2015). doi:10.1038/nature14613
Authors: Trevor R. Sorrells, Lauren N. Booth, Brian B. Tuch & Alexander D. Johnson
Epistasis—the non-additive interactions between different genetic loci—constrains evolutionary pathways, blocking some and permitting others. For biological networks such as transcription circuits, the nature of these constraints and their consequences are largely unknown. Here we describe the evolutionary pathways of a transcription network that controls the response to mating pheromone in yeast. A component of this network, the transcription regulator Ste12, has evolved two different modes of binding to a set of its target genes. In one group of species, Ste12 binds to specific DNA binding sites, while in another lineage it occupies DNA indirectly, relying on a second transcription regulator to recognize DNA. We show, through the construction of various possible evolutionary intermediates, that evolution of the direct mode of DNA binding was not directly accessible to the ancestor. Instead, it was contingent on a lineage-specific change to an overlapping transcription network with a different function, the specification of cell type. These results show that analysing and predicting the evolution of cis-regulatory regions requires an understanding of their positions in overlapping networks, as this placement constrains the available evolutionary pathways.
Ag29(BDT)12(TPP)4: A Tetravalent Nanocluster
by Joshua J. Hamilton, Montserrat Calixto Contreras, Jennifer L. ReedMicroorganisms in nature do not exist in isolation but rather interact with other species in their environment. Some microbes interact via syntrophic associations, in which the metabolic by-products of one species serve as nutrients for another. These associations sustain a variety of natural communities, including those involved in methanogenesis. In anaerobic syntrophic communities, energy is transferred from one species to another, either through direct contact and exchange of electrons, or through small molecule diffusion. Thermodynamics plays an important role in governing these interactions, as the oxidation reactions carried out by the first community member are only possible because degradation products are consumed by the second community member. This work presents the development and analysis of genome-scale network reconstructions of the bacterium Syntrophobacter fumaroxidans and the methanogenic archaeon Methanospirillum hungatei. The models were used to verify proposed mechanisms of ATP production within each species. We then identified additional constraints and the cellular objective function required to match experimental observations. The thermodynamic S. fumaroxidans model could not explain why S. fumaroxidans does not produce H2 in monoculture, indicating that current methods might not adequately estimate the thermodynamics, or that other cellular processes (e.g., regulation) play a role. We also developed a thermodynamic coculture model of the association between the organisms. The coculture model correctly predicted the exchange of both H2 and formate between the two species and suggested conditions under which H2 and formate produced by S. fumaroxidans would be fully consumed by M. hungatei.
by Bethany L. Dearlove, Simon D. W. FrostPrevious work has shown that asymmetry in viral phylogenies may be indicative of heterogeneity in transmission, for example due to acute HIV infection or the presence of ‘core groups’ with higher contact rates. Hence, evidence of asymmetry may provide clues to underlying population structure, even when direct information on, for example, stage of infection or contact rates, are missing. However, current tests of phylogenetic asymmetry (a) suffer from false positives when the tips of the phylogeny are sampled at different times and (b) only test for global asymmetry, and hence suffer from false negatives when asymmetry is localised to part of a phylogeny. We present a simple permutation-based approach for testing for asymmetry in a phylogeny, where we compare the observed phylogeny with random phylogenies with the same sampling and coalescence times, to reduce the false positive rate. We also demonstrate how profiles of measures of asymmetry calculated over a range of evolutionary times in the phylogeny can be used to identify local asymmetry. In combination with different metrics of asymmetry, this combined approach offers detailed insights of how phylogenies reconstructed from real viral datasets may deviate from the simplistic assumptions of commonly used coalescent and birth-death process models.
Predicting Binding Free Energy Change Caused by Point Mutations with Knowledge-Modified MM/PBSA Method
by Marharyta Petukh, Minghui Li, Emil AlexovA new methodology termed Single Amino Acid Mutation based change in Binding free Energy (SAAMBE) was developed to predict the changes of the binding free energy caused by mutations. The method utilizes 3D structures of the corresponding protein-protein complexes and takes advantage of both approaches: sequence- and structure-based methods. The method has two components: a MM/PBSA-based component, and an additional set of statistical terms delivered from statistical investigation of physico-chemical properties of protein complexes. While the approach is rigid body approach and does not explicitly consider plausible conformational changes caused by the binding, the effect of conformational changes, including changes away from binding interface, on electrostatics are mimicked with amino acid specific dielectric constants. This provides significant improvement of SAAMBE predictions as indicated by better match against experimentally determined binding free energy changes over 1300 mutations in 43 proteins. The final benchmarking resulted in a very good agreement with experimental data (correlation coefficient 0.624) while the algorithm being fast enough to allow for large-scale calculations (the average time is less than a minute per mutation).
Design of Protein Multi-specificity Using an Independent Sequence Search Reduces the Barrier to Low Energy Sequences
by Alexander M. Sevy, Tim M. Jacobs, James E. Crowe, Jens MeilerComputational protein design has found great success in engineering proteins for thermodynamic stability, binding specificity, or enzymatic activity in a ‘single state’ design (SSD) paradigm. Multi-specificity design (MSD), on the other hand, involves considering the stability of multiple protein states simultaneously. We have developed a novel MSD algorithm, which we refer to as REstrained CONvergence in multi-specificity design (RECON). The algorithm allows each state to adopt its own sequence throughout the design process rather than enforcing a single sequence on all states. Convergence to a single sequence is encouraged through an incrementally increasing convergence restraint for corresponding positions. Compared to MSD algorithms that enforce (constrain) an identical sequence on all states the energy landscape is simplified, which accelerates the search drastically. As a result, RECON can readily be used in simulations with a flexible protein backbone. We have benchmarked RECON on two design tasks. First, we designed antibodies derived from a common germline gene against their diverse targets to assess recovery of the germline, polyspecific sequence. Second, we design “promiscuous”, polyspecific proteins against all binding partners and measure recovery of the native sequence. We show that RECON is able to efficiently recover native-like, biologically relevant sequences in this diverse set of protein complexes.
Small-scale filament eruptions as the driver of X-ray jets in solar coronal holes
Nature 523, 7561 (2015). doi:10.1038/nature14556
Authors: Alphonse C. Sterling, Ronald L. Moore, David A. Falconer & Mitzi Adams
Solar X-ray jets are thought to be made by a burst of reconnection of closed magnetic field at the base of a jet with ambient open field. In the accepted version of the ‘emerging-flux’ model, such a reconnection occurs at a plasma current sheet between the open field and the emerging closed field, and also forms a localized X-ray brightening that is usually observed at the edge of the jet’s base. Here we report high-resolution X-ray and extreme-ultraviolet observations of 20 randomly selected X-ray jets that form in coronal holes at the Sun’s poles. In each jet, contrary to the emerging-flux model, a miniature version of the filament eruptions that initiate coronal mass ejections drives the jet-producing reconnection. The X-ray bright point occurs by reconnection of the ‘legs’ of the minifilament-carrying erupting closed field, analogous to the formation of solar flares in larger-scale eruptions. Previous observations have found that some jets are driven by base-field eruptions, but only one such study, of only one jet, provisionally questioned the emerging-flux model. Our observations support the view that solar filament eruptions are formed by a fundamental explosive magnetic process that occurs on a vast range of scales, from the biggest mass ejections and flare eruptions down to X-ray jets, and perhaps even down to smaller jets that may power coronal heating. A similar scenario has previously been suggested, but was inferred from different observations and based on a different origin of the erupting minifilament.
Structural Model of RNA Polymerase II Elongation Complex with Complete Transcription Bubble Reveals NTP Entry Routes
by Lu Zhang, Daniel-Adriano Silva, Fátima Pardo-Avila, Dong Wang, Xuhui HuangThe RNA polymerase II (Pol II) is a eukaryotic enzyme that catalyzes the synthesis of the messenger RNA using a DNA template. Despite numerous biochemical and biophysical studies, it remains elusive whether the “secondary channel” is the only route for NTP to reach the active site of the enzyme or if the “main channel” could be an alternative. On this regard, crystallographic structures of Pol II have been extremely useful to understand the structural basis of transcription, however, the conformation of the unpaired non-template DNA part of the full transcription bubble (TB) is still unknown. Since diffusion routes of the nucleoside triphosphate (NTP) substrate through the main channel might overlap with the TB region, gaining structural information of the full TB is critical for a complete understanding of Pol II transcription process. In this study, we have built a structural model of Pol II with a complete transcription bubble based on multiple sources of existing structural data and used Molecular Dynamics (MD) simulations together with structural analysis to shed light on NTP entry pathways. Interestingly, we found that although both channels have enough space to allow NTP loading, the percentage of MD conformations containing enough space for NTP loading through the secondary channel is twice higher than that of the main channel. Further energetic study based on MD simulations with NTP loaded in the channels has revealed that the diffusion of the NTP through the main channel is greatly disfavored by electrostatic repulsion between the NTP and the highly negatively charged backbones of nucleotides in the non-template DNA strand. Taken together, our results suggest that the secondary channel is the major route for NTP entry during Pol II transcription.
by Ruth Nussinov, Sebastian Bonhoeffer, Jason A. Papin, Olaf Sporns
by Olivier Marre, Vicente Botella-Soler, Kristina D. Simmons, Thierry Mora, Gašper Tkačik, Michael J. BerryMotion tracking is a challenge the visual system has to solve by reading out the retinal population. It is still unclear how the information from different neurons can be combined together to estimate the position of an object. Here we recorded a large population of ganglion cells in a dense patch of salamander and guinea pig retinas while displaying a bar moving diffusively. We show that the bar’s position can be reconstructed from retinal activity with a precision in the hyperacuity regime using a linear decoder acting on 100+ cells. We then took advantage of this unprecedented precision to explore the spatial structure of the retina’s population code. The classical view would have suggested that the firing rates of the cells form a moving hill of activity tracking the bar’s position. Instead, we found that most ganglion cells in the salamander fired sparsely and idiosyncratically, so that their neural image did not track the bar. Furthermore, ganglion cell activity spanned an area much larger than predicted by their receptive fields, with cells coding for motion far in their surround. As a result, population redundancy was high, and we could find multiple, disjoint subsets of neurons that encoded the trajectory with high precision. This organization allows for diverse collections of ganglion cells to represent high-accuracy motion information in a form easily read out by downstream neural circuits.
Rigidity Emerges during Antibody Evolution in Three Distinct Antibody Systems: Evidence from QSFR Analysis of Fab Fragments
by Tong Li, Malgorzata B. Tracka, Shahid Uddin, Jose Casas-Finet, Donald J. Jacobs, Dennis R. LivesayThe effects of somatic mutations that transform polyspecific germline (GL) antibodies to affinity mature (AM) antibodies with monospecificity are compared among three GL-AM Fab pairs. In particular, changes in conformational flexibility are assessed using a Distance Constraint Model (DCM). We have previously established that the DCM can be robustly applied across a series of antibody fragments (VL to Fab), and subsequently, the DCM was combined with molecular dynamics (MD) simulations to similarly characterize five thermostabilizing scFv mutants. The DCM is an ensemble based statistical mechanical approach that accounts for enthalpy/entropy compensation due to network rigidity, which has been quite successful in elucidating conformational flexibility and Quantitative Stability/Flexibility Relationships (QSFR) in proteins. Applied to three disparate antibody systems changes in QSFR quantities indicate that the VH domain is typically rigidified, whereas the VL domain and CDR L2 loop become more flexible during affinity maturation. The increase in CDR H3 loop rigidity is consistent with other studies in the literature. The redistribution of conformational flexibility is largely controlled by nonspecific changes in the H-bond network, although certain Arg to Asp salt bridges create highly localized rigidity increases. Taken together, these results reveal an intricate flexibility/rigidity response that accompanies affinity maturation.
The prediction of protein domain region is an advantageous process on the study of protein structure and function. In this study, we proposed a new method, which is composed of fuzzy mean operator and region division, to predict the particular positions of domains in a target protein based on its sequence. The whole sequence is aligned and scored by using fuzzy mean operator, and the final determination of domain region position is realized by region division. A published benchmark is used for the comparison with previous researches. In addition, we generate two extra datasets to examine the stability of this method. Finally, the prediction accuracy of independent test dataset achieved by our method was up to 84.13%. We wish that this method could be useful for related researches. Proteins 2015; 83:1462–1469. © 2015 Wiley Periodicals, Inc.