Structural basis for synthesis of inflammatory mediators by human leukotriene C4 synthase

Cysteinyl leukotrienes are key mediators in inflammation and have an important role in acute and chronic inflammatory diseases of the cardiovascular and respiratory systems, in particular bronchial asthma. In the biosynthesis of cysteinyl leukotrienes, conversion of arachidonic acid forms the unstable epoxide leukotriene A4 (LTA4). This intermediate is conjugated with glutathione (GSH) to produce leukotriene C4 (LTC4) in a reaction catalysed by LTC4 synthase: this reaction is the key step in cysteinyl leukotriene formation. Here we present the crystal structure of the human LTC4 synthase in its apo and GSH-complexed forms to 2.00 and 2.15 A resolution, respectively. The structure reveals a homotrimer, where each monomer is composed of four transmembrane segments. The structure of the enzyme in complex with substrate reveals that the active site enforces a horseshoe-shaped conformation on GSH, and effectively positions the thiol group for activation by a nearby arginine at the membrane-enzyme interface. In addition, the structure provides a model for how the omega-end of the lipophilic co-substrate is pinned at one end of a hydrophobic cleft, providing a molecular 'ruler' to align the reactive epoxide at the thiol of glutathione. This provides new structural insights into the mechanism of LTC4 formation, and also suggests that the observed binding and activation of GSH might be common for a family of homologous proteins important for inflammatory and detoxification responses.     

Biodiversity and ecosystem multifunctionality

Biodiversity loss can affect ecosystem functions and services. Individual ecosystem functions generally show a positive asymptotic relationship with increasing biodiversity, suggesting that some species are redundant. However, ecosystems are managed and conserved for multiple functions, which may require greater biodiversity. Here we present an analysis of published data from grassland biodiversity experiments, and show that ecosystem multifunctionality does require greater numbers of species. We analysed each ecosystem function alone to identify species with desirable effects. We then calculated the number of species with positive effects for all possible combinations of functions. Our results show appreciable differences in the sets of species influencing different ecosystem functions, with average proportional overlap of about 0.2 to 0.5. Consequently, as more ecosystem processes were included in our analysis, more species were found to affect overall functioning. Specifically, for all of the analysed experiments, there was a positive saturating relationship between the number of ecosystem processes considered and the number of species influencing overall functioning. We conclude that because different species often influence different functions, studies focusing on individual processes in isolation will underestimate levels of biodiversity required to maintain multifunctional ecosystems.     

Catastrophic flooding origin of shelf valley systems in the English Channel

Megaflood events involving sudden discharges of exceptionally large volumes of water are rare, but can significantly affect landscape evolution, continental-scale drainage patterns and climate change. It has been proposed that a significant flood event eroded a network of large ancient valleys on the floor of the English Channel-the narrow seaway between England and France. This hypothesis has remained untested through lack of direct evidence, and alternative non-catastrophist ideas have been entertained for valley formation. Here we analyse a new regional bathymetric map of part of the English Channel derived from high-resolution sonar data, which shows the morphology of the valley in unprecedented detail. We observe a large bedrock-floored valley that contains a distinct assemblage of landforms, including streamlined islands and longitudinal erosional grooves, which are indicative of large-scale subaerial erosion by high-magnitude water discharges. Our observations support the megaflood model, in which breaching of a rock dam at the Dover Strait instigated catastrophic drainage of a large pro-glacial lake in the southern North Sea basin. We suggest that megaflooding provides an explanation for the permanent isolation of Britain from mainland Europe during interglacial high-sea-level stands, and consequently for patterns of early human colonisation of Britain together with the large-scale reorganization of palaeodrainage in northwest Europe.     

Natural history and evolutionary principles of gene duplication in fungi

Gene duplication and loss is a powerful source of functional innovation. However, the general principles that govern this process are still largely unknown. With the growing number of sequenced genomes, it is now possible to examine these events in a comprehensive and unbiased manner. Here, we develop a procedure that resolves the evolutionary history of all genes in a large group of species. We apply our procedure to seventeen fungal genomes to create a genome-wide catalogue of gene trees that determine precise orthology and paralogy relations across these species. We show that gene duplication and loss is highly constrained by the functional properties and interacting partners of genes. In particular, stress-related genes exhibit many duplications and losses, whereas growth-related genes show selection against such changes. Whole-genome duplication circumvents this constraint and relaxes the dichotomy, resulting in an expanded functional scope of gene duplication. By characterizing the functional fate of duplicate genes we show that duplicated genes rarely diverge with respect to biochemical function, but typically diverge with respect to regulatory control. Surprisingly, paralogous modules of genes rarely arise, even after whole-genome duplication. Rather, gene duplication may drive the modularization of functional networks through specialization, thereby disentangling cellular systems.