Crystal structure of the membrane attack complex assembly inhibitor BGA71 from the Lyme disease agent Borrelia bavariensis

Funding Information: This work was supported by the European Regional Development Fund (ERDF) grant Nr. 1.1.1.2/VIAA/1/16/144 “Structural and functional studies of Lyme disease agent Borrelia burgdorferi outer surface proteins to reveal the mechanisms of pathogenesis with the intention to create a new vaccine”. Diffraction data have been collected on BL14.1 at the BESSY II electron storage ring operated by the Helmholtz-Zentrum, Berlin. We would particularly like to acknowledge the help and support of Manfred S. Weiss and Christian Feiler during the experiment. Publisher Copyright: © 2018, The Author(s).Borrelia (B.) bavariensis, B. burgdorferi, B. afzelii, B. garinii, B. spielmanii, and B. mayonii are the causative agents in Lyme disease. Lyme disease spirochetes reside in infected Ixodes ticks and are transferred to mammalian hosts during tick feeding. Once transmitted, spirochetes must overcome the first line of defense of the innate immune system either by binding complement regulators or by terminating the formation of the membrane attack complex (MAC). In B. bavariensis, the proteins BGA66 and BGA71 inhibit complement activation by interacting with the late complement components C7, C8, and C9, as well as with the formed MAC. In this study, we have determined the crystal structure of the potent MAC inhibitor BGA71 at 2.9 Ǻ resolution. The structure revealed a cysteine cross-linked homodimer. Based on the crystal structure of BGA71 and the structure-based sequence alignment with CspA from B. burgdorferi, we have proposed a potential binding site for C7 and C9, both of which are constituents of the formed MAC. Our results shed light on the molecular mechanism of immune evasion developed by the human pathogenic Borrelia species to overcome innate immunity. These results will aid in the understanding of Lyme disease pathogenesis and pave the way for the development of new strategies to prevent Lyme disease.publishersversionPeer reviewe

Discovering cancer genes by integrating network and functional properties

<p>Abstract</p> <p>Background</p> <p>Identification of novel cancer-causing genes is one of the main goals in cancer research. The rapid accumulation of genome-wide protein-protein interaction (PPI) data in humans has provided a new basis for studying the topological features of cancer genes in cellular networks. It is important to integrate multiple genomic data sources, including PPI networks, protein domains and Gene Ontology (GO) annotations, to facilitate the identification of cancer genes.</p> <p>Methods</p> <p>Topological features of the PPI network, as well as protein domain compositions, enrichment of gene ontology categories, sequence and evolutionary conservation features were extracted and compared between cancer genes and other genes. The predictive power of various classifiers for identification of cancer genes was evaluated by cross validation. Experimental validation of a subset of the prediction results was conducted using siRNA knockdown and viability assays in human colon cancer cell line DLD-1.</p> <p>Results</p> <p>Cross validation demonstrated advantageous performance of classifiers based on support vector machines (SVMs) with the inclusion of the topological features from the PPI network, protein domain compositions and GO annotations. We then applied the trained SVM classifier to human genes to prioritize putative cancer genes. siRNA knock-down of several SVM predicted cancer genes displayed greatly reduced cell viability in human colon cancer cell line DLD-1.</p> <p>Conclusion</p> <p>Topological features of PPI networks, protein domain compositions and GO annotations are good predictors of cancer genes. The SVM classifier integrates multiple features and as such is useful for prioritizing candidate cancer genes for experimental validations.</p

Pan-cancer analysis of whole genomes

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale(1-3). Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter(4); identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6); analyses timings and patterns of tumour evolution(7); describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9); and evaluates a range of more-specialized features of cancer genomes(8,10-18).Peer reviewe

A novel fold for the factor H-binding protein BbCRASP-1 of Borrelia burgdorferi.

Borrelia burgdorferi, a spirochete transmitted to human hosts during feeding of infected Ixodes ticks, is the causative agent of Lyme disease. Serum-resistant B. burgdorferi strains cause a chronic, multisystemic form of the disease and bind complement factor H (FH) and FH-like protein 1 (FHL-1) on the spirochete surface. Here we report the atomic structure for the key FHL-1- and FH-binding protein BbCRASP-1 and reveal a homodimer that presents a novel target for drug design

Structure-function mapping of BbCRASP-1, the key complement factor H and FHL-1 binding protein of Borrelia burgdorferi.

Borrelia burgdorferi, a spirochaete transmitted to human hosts during feeding of infected Ixodes ticks, is the causative agent of Lyme disease, the most frequent vector-borne disease in Eurasia and North America. Sporadically Lyme disease develops into a chronic, multisystemic disorder. Serum-resistant B. burgdorferi strains bind complement factor H (FH) and FH-like protein 1 (FHL-1) on the spirochaete surface. This binding is dependent on the expression of proteins termed complement-regulator acquiring surface proteins (CRASPs). The atomic structure of BbCRASP-1, the key FHL-1/FH-binding protein of B. burgdorferi, has recently been determined. Our analysis indicates that its protein topology apparently evolved to provide a high affinity interaction site for FH/FHL-1 and leads to an atomic-level hypothesis for the functioning of BbCRASP-1. This work demonstrates that pathogens interact with complement regulators in ways that are distinct from the mechanisms used by the host and are thus obvious targets for drug design

Biogeography and Potential Exchanges Among the Atlantic Equatorial Belt Cold-Seep Faunas

Like hydrothermal vents along oceanic ridges, cold seeps are patchy and isolated ecosystems along continental margins, extending from bathyal to abyssal depths. The Atlantic Equatorial Belt (AEB), from the Gulf of Mexico to the Gulf of Guinea, was one focus of the Census of Marine Life ChEss (Chemosynthetic Ecosystems) program to study biogeography of seep and vent fauna. We present a review and analysis of collections from five seep regions along the AEB: the Gulf of Mexico where extensive faunal sampling has been conducted from 400 to 3300m, the Barbados accretionary prism, the Blake ridge diapir, and in the Eastern Atlantic from the Congo and Gabon margins and the recently explored Nigeria margin. Of the 72 taxa identified at the species level, a total of 9 species or species complexes are identified as amphi-Atlantic. Similarity analyses based on both Bray Curtis and Hellinger distances among 9 faunal collections, and principal component analysis based on presence/absence of megafauna species at these sites, suggest that within the AEB seep megafauna community structure is influenced primarily by depth rather than by geographic distance. Depth segregation is observed between 1000 and 2000m, with the middle slope sites either grouped with those deeper than 2000m or with the shallower sites. The highest level of community similarity was found between the seeps of the Florida escarpment and Congo margin. In the western Atlantic, the highest degree of similarity is observed between the shallowest sites of the Barbados prism and of the Louisiana slope. The high number of amphi-atlantic cold-seep species that do not cluster according to biogeographic regions, and the importance of depth in structuring AEB cold-seep communities are the major conclusions of this study. The hydrothermal vent sites along the Mid Atlantic Ridge (MAR) did not appear as “stepping stones” for dispersal of the AEB seep fauna, however, the south MAR and off axis regions should be further explored to more fully test this hypothesis