Prediction of host - pathogen protein interactions between Mycobacterium tuberculosis and Homo sapiens using sequence motifs

Huo, Tong; Liu, Wei; Guo, Yu; Yang, Cheng; Lin, Jianping; Rao, Zihe

doi:10.1186/s12859-015-0535-y

Cited by 52 publications

(39 citation statements)

References 79 publications

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“…Some earlier studies have also proposed the use of domain-level interaction information to screen for potential PPIs, but those approaches essentially treat all members of a domain family on the same footing, disregarding the differences in interaction ability among them [32, 33, 66–69]. Thus, all occurrences of a pair of domains that could potentially interact are weighted equally.…”

Section: Discussionmentioning

confidence: 99%

Using structural knowledge in the protein data bank to inform the search for potential host-microbe protein interactions in sequence space: application to Mycobacterium tuberculosis

Mahajan

Mande

2017

BMC Bioinformatics

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BackgroundA comprehensive map of the human-M. tuberculosis (MTB) protein interactome would help fill the gaps in our understanding of the disease, and computational prediction can aid and complement experimental studies towards this end. Several sequence-based in silico approaches tap the existing data on experimentally validated protein-protein interactions (PPIs); these PPIs serve as templates from which novel interactions between pathogen and host are inferred. Such comparative approaches typically make use of local sequence alignment, which, in the absence of structural details about the interfaces mediating the template interactions, could lead to incorrect inferences, particularly when multi-domain proteins are involved.ResultsWe propose leveraging the domain-domain interaction (DDI) information in PDB complexes to score and prioritize candidate PPIs between host and pathogen proteomes based on targeted sequence-level comparisons. Our method picks out a small set of human-MTB protein pairs as candidates for physical interactions, and the use of functional meta-data suggests that some of them could contribute to the in vivo molecular cross-talk between pathogen and host that regulates the course of the infection. Further, we present numerical data for Pfam domain families that highlights interaction specificity on the domain level. Not every instance of a pair of domains, for which interaction evidence has been found in a few instances (i.e. structures), is likely to functionally interact. Our sorting approach scores candidates according to how “distant” they are in sequence space from known examples of DDIs (templates). Thus, it provides a natural way to deal with the heterogeneity in domain-level interactions.ConclusionsOur method represents a more informed application of local alignment to the sequence-based search for potential human-microbial interactions that uses available PPI data as a prior. Our approach is somewhat limited in its sensitivity by the restricted size and diversity of the template dataset, but, given the rapid accumulation of solved protein complex structures, its scope and utility are expected to keep steadily improving.Electronic supplementary materialThe online version of this article (doi:10.1186/s12859-017-1550-y) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Using structural knowledge in the protein data bank to inform the search for potential host-microbe protein interactions in sequence space: application to Mycobacterium tuberculosis

Mahajan

Mande

2017

BMC Bioinformatics

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“…Three fractions (1–3) were examined from gel filtration of peak 1 (fractions #15—19) from anion exchange. Fraction 1 (#44–48) contained the presence of Encapsulin (red, circled), while fractions 2 (#49–53) and 3 (#54–58) contained a triangle-shaped average protein complex (purple, circled).…”

Section: Supplementary Figuresmentioning

confidence: 99%

“… (a) Cell culture filtrate was separated by anion exchange which yielded three fractions (1–3). A silver-stained 8–15% gradient SDS-PAGE gel showed that fractions 1 and 2 contained the predominant amount of encapsulin.…”

Section: Supplementary Figuresmentioning

confidence: 99%

Structural investigation of Mycobacterial protein complexes involved in the stationary phase stress response

Kirykowicz

Woodward

2020

Preprint

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36Large protein complexes play key roles in mediating biological processes in the cell. Little 37 structural information is known on the protein complex mediators governing persistence in the 38 host for Mycobacterium tuberculosis (Mtb). We applied the 'shotgun EM' method for the 39 structural characterisation of protein complexes produced after exposure to stationary phase 40 stress for the model Mycobacterium, M smegmatis (Msm). We identified glutamine synthetase 41 I, essential for Mtb virulence, in addition to bacterioferritin, critical for Mtb iron regulation, 42 and encapsulin, which produces a cage-like structure to enclose target proteins. Further 43 investigation found that encapsulin carries dye-decolourising peroxidase (DyP), a potent 44 protein antioxidant, as the primary cargo during stationary phase stress. Our 'proof-of-concept' 45 application of this method offers insight into identifying potential key-mediators in Mtb 46 persistence. 47 immune response (1). Although some studies have shown potential key mediators in Mtb 53 survival in the host (2-4) there is a lack of structural information to guide drug discovery or 54 elucidate biological function. 55 56Structural data provides compelling evidence for the existence of protein complexes which are 57 physiologically relevant to the cell. In addition, this data offers valuable information on subunit 58 composition and mechanism of interaction, which yields biological insight governing its 59 potential actions (5). Single-particle transmission electron microscopy (TEM) is a powerful 60 3 method to reconstruct large protein complexes. The method has been successfully used to solve 61 the structures of protein complexes in a range of organisms from homogenous (6) as well as 62 heterogenous (7-10) samples. Combining 3D reconstruction of protein complexes from 63negative stain EM images with information obtained from mass spectrometry data ('shotgun 64 EM') (10) allows for a potentially high-throughput approach to finding complexes which could 65 play a key role in Mtb pathogenesis. 66 67 Although the 'shotgun EM' approach offers a faster method for solving the structures of a range 68 of protein complexes without the need for extensive purification (11), the approach still needs 69 to be tested and adapted for the organism of application (9,10,12). Here, we present our 70 'shotgun EM' methodology for the purification and TEM 3D reconstruction of Mycobacterial 71protein complexes from the model organism, M smegmatis (Msm), after exposure to stationary 72 phase stress which is known to induce a protective effect against subsequent exposure to 73 oxidative stress (13). We identified three protein complexes (glutamine synthetase I (GSI) (E.C 74 6.3.1.2), bacterioferritin (BrfA) (E.C 1.16.3.1), and encapsulin); the initial identity assigned by 75 mass spectrometry, as well as the 3D model and subunit composition, was validated by fitting 76 of homologous crystallographic structures into the low-resolution density. We demonstrate that 77 encapsulin encloses...

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“…In the line of exploring computational tools to design and developing novel drugs against Mtb, Huo et al [49] developed a systematic flow to predict the interaction between Mtb and H. sapiens based upon sequence motifs. Protein sequences were used as an initial input to identify the interaction between Mtb and H. sapiens by 'interolog' method and further filtered by domain-domain interactions (DDIs) prediction.…”

Section: Anti-tubercular Peptides and Mtb: A Computational Approachmentioning

confidence: 99%

Neoteric advancement in TB drugs and an overview on the anti-tubercular role of peptides through computational approaches

Khusro¹,

Aarti²,

Barbabosa‐Pliego

et al. 2018

Microbial Pathogenesis

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Tuberculosis (TB) is a devastating threat to human health whose treatment without the emergence of drug resistant Mycobacterium tuberculosis (M. tuberculosis) is the million-dollar question at present. The pathogenesis of M. tuberculosis has been extensively studied which represents unique defence strategies by infecting macrophages. Several anti-tubercular drugs with varied mode of action and administration from diversified sources have been used for the treatment of TB that later contributed to the emergence of multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB). However, few of potent anti-tubercular drugs are scheduled for clinical trials status in 2017-2018. Peptides of varied origins such as human immune cells and non-immune cells, bacteria, fungi, and venoms have been widely investigated as anti-tubercular agents for the replacement of existing anti-tubercular drugs in future. In the present review, we spotlighted not only on the mechanisms of action and mode of administration of currently available anti-tubercular drugs but also the recent comprehensive report of World Health Organization (WHO) on TB epidemic, diagnosis, prevention, and treatment. The major excerpt of the study also inspects the direct contribution of different computational tools during drug designing strategies against M. tuberculosis in order to grasp the interplay between anti-tubercular peptides and targeted bacterial protein. The potentiality of some of these anti-tubercular peptides as therapeutic agents unlocks a new portal for achieving the goal of end TB strategy.

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Prediction of host - pathogen protein interactions between Mycobacterium tuberculosis and Homo sapiens using sequence motifs

Cited by 52 publications

References 79 publications

Using structural knowledge in the protein data bank to inform the search for potential host-microbe protein interactions in sequence space: application to Mycobacterium tuberculosis

Using structural knowledge in the protein data bank to inform the search for potential host-microbe protein interactions in sequence space: application to Mycobacterium tuberculosis

Structural investigation of Mycobacterial protein complexes involved in the stationary phase stress response

Neoteric advancement in TB drugs and an overview on the anti-tubercular role of peptides through computational approaches

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