Abstract
BackgroundThe TlyA protein has a controversial function as a virulence factor in Mycobacterium tuberculosis (M. tuberculosis). At present, its dual activity as hemolysin and RNA methyltransferase in M. tuberculosis has been indirectly proposed based on in vitro results. There is no evidence however for TlyA relevance in the survival of tubercle bacilli inside host cells or whether both activities are functionally linked. A thorough analysis of structure prediction for this mycobacterial protein in this study shows the need for reevaluating TlyA's function in virulence.ResultsBioinformatics analysis of TlyA identified a ribosomal protein binding domain (S4 domain), located between residues 5 and 68 as well as an FtsJ-like methyltranferase domain encompassing residues 62 and 247, all of which have been previously described in translation machinery-associated proteins. Subcellular localization prediction showed that TlyA lacks a signal peptide and its hydrophobicity profile showed no evidence of transmembrane helices. These findings suggested that it may not be attached to the membrane, which is consistent with a cytoplasmic localization. Three-dimensional modeling of TlyA showed a consensus structure, having a common core formed by a six-stranded β-sheet between two α-helix layers, which is consistent with an RNA methyltransferase structure. Phylogenetic analyses showed high conservation of the tlyA gene among Mycobacterium species. Additionally, the nucleotide substitution rates suggested purifying selection during tlyA gene evolution and the absence of a common ancestor between TlyA proteins and bacterial pore-forming proteins.ConclusionAltogether, our manual in silico curation suggested that TlyA is involved in ribosomal biogenesis and that there is a functional annotation error regarding this protein family in several microbial and plant genomes, including the M. tuberculosis genome.
Highlights
The TlyA protein has a controversial function as a virulence factor in Mycobacterium tuberculosis (M. tuberculosis)
These M. tuberculosis-related TlyA protein sequences are mainly classified as hemolysin A inside the FtsJ-like class based on domain similarity and have been annotated as such in Genbank, EMBL, UniProt and SWISSPROT databases according to sequence similarity with Serpulina hyodysenteriae TlyA annotated as being a hemolysin
TlyA amino acid sequences from M. tuberculosis H37Rv, H37Ra, CDC1551, M. bovis and M. bovis-BCG reference strain alignment showed a 100% identity with the Harleem, F11 and C M. tuberculosis strains (Figure 1B)
Summary
The TlyA protein has a controversial function as a virulence factor in Mycobacterium tuberculosis (M. tuberculosis). When RIF and INH are ineffective, standard treatment guidelines recommend a combination of second-line drugs [3]. Among these therapeutic choices, aminoglycosides such as Capreomycin (CMN) and Viomycin (VMN) are given in combination with other antibiotics to treat multidrug-resistant strains (MDR); they are effective against non-replicating M. tuberculosis strains, as well as being useful in the treatment of latent TB infections [4]. CMN- and VMN-resistant bacilli are classified as XDR-TB strains and are a cause of major concern since these drugs have more toxic side effects and might result in higher death rates, especially among HIV-infected persons [1]
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