Browsing by Subject "Proteome"

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    Open Access
    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.
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    Projection of gene-protein networks to the functional space of the proteome and its application to analysis of organism complexity
    (BioMed Central Ltd, 2010) Kanapin, Alexander; Mulder, Nicola; Kuznetsov, Vladimir
    We consider the problem of biological complexity via a projection of protein-coding genes of complex organisms onto the functional space of the proteome. The latter can be defined as a set of all functions committed by proteins of an organism. Alternative splicing (AS) allows an organism to generate diverse mature RNA transcripts from a single mRNA strand and thus it could be one of the key mechanisms of increasing of functional complexity of the organism's proteome and a driving force of biological evolution. Thus, the projection of transcription units (TU) and alternative splice-variant (SV) forms onto proteome functional space could generate new types of relational networks (e.g. SV-protein function networks, SFN) and lead to discoveries of novel evolutionarily conservative functional modules. Such types of networks might provide new reliable characteristics of organism complexity and a better understanding of the evolutionary integration and plasticity of interconnection of genome-transcriptome-proteome functions. RESULTS: We use the InterPro and UniProt databases to attribute descriptive features (keywords) to protein sequences. UniProt database includes a controlled and curated vocabulary of specific descriptors or keywords. The keywords have been assigned to a protein sequence via conserved domains or via similarity with annotated sequences. Then we consider the unique combinations of keywords as the protein functional labels (FL), which characterize the biological functions of the given protein and construct the contingency tables and graphs providing the projections of transcription units (TU) and alternative splice-variants (SV) onto all FL of the proteome of a given organism. We constructed SFNs for organisms with different evolutionary history and levels of complexity, and performed detailed statistical parameterization of the networks. CONCLUSIONS: The application of the algorithm to organisms with different evolutionary history and level of biological complexity (nematode, fruit fly, vertebrata) reveals that the parameters describing SFN correlate with the complexity of a given organism. Using statistical analysis of the links of the functional networks, we propose new features of evolution of protein function acquisition. We reveal a group of genes and corresponding functions, which could be attributed to an early conservative part of the cellular machinery essential for cell viability and survival. We identify and provide characteristics of functional switches in the polyform group of TUs in different organisms. Based on comparison of mouse and human SFNs, a role of alternative splicing as a necessary source of evolution towards more complex organisms is demonstrated.The entire set of FL across many organisms could be used as a draft of the catalogue of the functional space of the proteome world.