Functional insights from proteome-wide structural modeling of Treponema pallidum subspecies pallidum, the causative agent of syphilis
| dc.contributor.author | Houston, Simon | |
| dc.contributor.author | Lithgow, Karen V | |
| dc.contributor.author | Osbak, Kara K | |
| dc.contributor.author | Kenyon, Chris R | |
| dc.contributor.author | Cameron, Caroline E | |
| dc.date.accessioned | 2018-05-21T06:52:23Z | |
| dc.date.available | 2018-05-21T06:52:23Z | |
| dc.date.issued | 2018-05-16 | |
| dc.date.updated | 2018-05-20T03:39:14Z | |
| dc.description.abstract | 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. | |
| dc.identifier.apacitation | Houston, S., Lithgow, K. V., Osbak, K. K., Kenyon, C. R., & Cameron, C. E. (2018). Functional insights from proteome-wide structural modeling of Treponema pallidum subspecies pallidum, the causative agent of syphilis. <i>BMC Structural Biology</i>, http://hdl.handle.net/11427/28101 | en_ZA |
| dc.identifier.chicagocitation | Houston, Simon, Karen V Lithgow, Kara K Osbak, Chris R Kenyon, and Caroline E Cameron "Functional insights from proteome-wide structural modeling of Treponema pallidum subspecies pallidum, the causative agent of syphilis." <i>BMC Structural Biology</i> (2018) http://hdl.handle.net/11427/28101 | en_ZA |
| dc.identifier.citation | BMC Structural Biology. 2018 May 16;18(1):7 | |
| dc.identifier.ris | TY - Journal Article AU - Houston, Simon AU - Lithgow, Karen V AU - Osbak, Kara K AU - Kenyon, Chris R AU - Cameron, Caroline E AB - 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. DA - 2018-05-16 DB - OpenUCT DP - University of Cape Town J1 - BMC Structural Biology LK - https://open.uct.ac.za PB - University of Cape Town PY - 2018 T1 - Functional insights from proteome-wide structural modeling of Treponema pallidum subspecies pallidum, the causative agent of syphilis TI - Functional insights from proteome-wide structural modeling of Treponema pallidum subspecies pallidum, the causative agent of syphilis UR - http://hdl.handle.net/11427/28101 ER - | en_ZA |
| dc.identifier.uri | https://doi.org/10.1186/s12900-018-0086-3 | |
| dc.identifier.uri | http://hdl.handle.net/11427/28101 | |
| dc.identifier.vancouvercitation | Houston S, Lithgow KV, Osbak KK, Kenyon CR, Cameron CE. Functional insights from proteome-wide structural modeling of Treponema pallidum subspecies pallidum, the causative agent of syphilis. BMC Structural Biology. 2018; http://hdl.handle.net/11427/28101. | en_ZA |
| dc.language.iso | en | |
| dc.publisher | BioMed Central | |
| dc.publisher.department | Division of Infectious Disease and HIV Med | en_ZA |
| dc.publisher.faculty | Faculty of Health Sciences | en_ZA |
| dc.publisher.institution | University of Cape Town | |
| dc.rights.holder | The Author(s). | |
| dc.source | BMC Structural Biology | |
| dc.source.uri | https://bmcstructbiol.biomedcentral.com/ | |
| dc.subject.other | Treponema pallidum | |
| dc.subject.other | Syphilis | |
| dc.subject.other | Proteome | |
| dc.subject.other | Structural modeling | |
| dc.subject.other | Functional annotation | |
| dc.subject.other | Virulence factors | |
| dc.title | Functional insights from proteome-wide structural modeling of Treponema pallidum subspecies pallidum, the causative agent of syphilis | |
| dc.type | Journal Article | |
| uct.type.filetype | Text | |
| uct.type.filetype | Image |