Browsing by Author "Lithgow, Karen V"

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    Characterizing the syphilis-causing Treponema pallidum ssp. pallidum proteome using complementary mass spectrometry
    (Public Library of Science, 2016) Osbak, Kara K; Houston, Simon; Lithgow, Karen V; Meehan, Conor J; Strouhal, Michal; Šmajs, David; Cameron, Caroline E; Van Ostade, Xaveer; Kenyon, Chris R; Van Raemdonck, Geert A
    Author Summary: Syphilis remains a major cause of morbidity and mortality worldwide. The bacterium causing syphilis, Treponema pallidum ssp. pallidum , has evolved into a highly distinctive organism that is only able survive (and be propagated) in mammals. In humans it can evade the immune system for decades with devastating consequences. Much remains to be learned about how it accomplishes this. Only a minority of its predicted proteins have been detected experimentally thus far. We aimed to more comprehensively characterize the proteins of this organism. Since it cannot be cultured in vitro , we cultured T . pallidum in rabbits and analyzed extracted proteins using different mass spectrometry methods, a manner of detecting proteins with high accuracy. In total, we detected more than half of the predicted number of proteins that could be expressed by this bacterium (N = 557). For approximately half of the proteins, we succeeded in characterizing their predicted cellular location using an array of bioinformatic tools and catalogued their function. This is the most comprehensive analysis of the T . pallidum proteome to date. This study lays the groundwork for other protein investigations of this unique organism.
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    Functional insights from proteome-wide structural modeling of Treponema pallidum subspecies pallidum, the causative agent of syphilis
    (BioMed Central, 2018-05-16) Houston, Simon; Lithgow, Karen V; Osbak, Kara K; Kenyon, Chris R; Cameron, Caroline E
    Background Syphilis continues to be a major global health threat with 11 million new infections each year, and a global burden of 36 million cases. The causative agent of syphilis, Treponema pallidum subspecies pallidum, is a highly virulent bacterium, however the molecular mechanisms underlying T. pallidum pathogenesis remain to be definitively identified. This is due to the fact that T. pallidum is currently uncultivatable, inherently fragile and thus difficult to work with, and phylogenetically distinct with no conventional virulence factor homologs found in other pathogens. In fact, approximately 30% of its predicted protein-coding genes have no known orthologs or assigned functions. Here we employed a structural bioinformatics approach using Phyre2-based tertiary structure modeling to improve our understanding of T. pallidum protein function on a proteome-wide scale. Results Phyre2-based tertiary structure modeling generated high-confidence predictions for 80% of the T. pallidum proteome (780/978 predicted proteins). Tertiary structure modeling also inferred the same function as primary structure-based annotations from genome sequencing pipelines for 525/605 proteins (87%), which represents 54% (525/978) of all T. pallidum proteins. Of the 175 T. pallidum proteins modeled with high confidence that were not assigned functions in the previously annotated published proteome, 167 (95%) were able to be assigned predicted functions. Twenty-one of the 175 hypothetical proteins modeled with high confidence were also predicted to exhibit significant structural similarity with proteins experimentally confirmed to be required for virulence in other pathogens. Conclusions Phyre2-based structural modeling is a powerful bioinformatics tool that has provided insight into the potential structure and function of the majority of T. pallidum proteins and helped validate the primary structure-based annotation of more than 50% of all T. pallidum proteins with high confidence. This work represents the first T. pallidum proteome-wide structural modeling study and is one of few studies to apply this approach for the functional annotation of a whole proteome.