The PE and PPE Protein Families of<i>Mycobacterium tuberculosis</i>

Delogu, Giovanni; Cole, Stewart T.; Brosch, Roland

doi:10.1002/9783527611614.ch7

Cited by 18 publications

(13 citation statements)

References 80 publications

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“…The polymorphic GC-rich sequences (PGRS), which were first identified as repetitive genetic sequences and used as a typing tool in molecular epidemiology studies [ 15 ], were discovered as proteins-coding sequences only following completion and assembly of the Mtb genome [ 11 ]. The Mtb genome contains 65 pe_pgrs genes, although only 51 of these express a functional protein, at least in Mtb H37Rv [ 16 ]. These genes are found in all members of MTBC and few other mycobacterial species that can cause diseases in humans as M. marinum (≈ 148 genes) and M. ulcerans (≈ 121 genes), although pe_pgrs genes in these species show significant differences with those found in MTBC [ 14 , 17 ].…”

Section: Introductionmentioning

confidence: 99%

PE_PGRS proteins ofMycobacterium tuberculosis: A specialized molecular task force at the forefront of host–pathogen interaction

et al. 2020

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To the PE_PGRS protein subfamily belongs a group of surface-exposed mycobacterial antigens that in Mycobacterium tuberculosis ( Mtb ) H37Rv accounts to more than 65 genes, 51 of which are thought to express a functional protein. PE_PGRS proteins share a conserved structural architecture with three main domains: the N-terminal PE domain; the PGRS domain, that can vary in sequence and size and is characterized by the presence of multiple GGA-GGX amino acid repeats; the highly conserved sequence containing the GRPLI motif that links the PE and PGRS domains; the unique C-terminus end that can vary in size from few to up to ≈ 300 amino acids. pe_pgrs genes emerged in slow-growing mycobacteria and expanded and diversified in MTBC and few other pathogenic mycobacteria. Interestingly, despite sequence homology and apparent redundancy, PE_PGRS proteins seem to have evolved a peculiar function. In this review, we summarize the actual knowledge on this elusive protein family in terms of evolution, structure, and function, focusing on the role of PE_PGRS in TB pathogenesis. We provide an original hypothesis on the role of the PE domain and propose a structural model for the polymorphic PGRS domain that might explain how so similar proteins can have different physiological functions.

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Section: Introductionmentioning

confidence: 99%

PE_PGRS proteins ofMycobacterium tuberculosis: A specialized molecular task force at the forefront of host–pathogen interaction

et al. 2020

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“…Many of the pe and ppe gene products are predicted to be localised to the cell membrane or secreted including those in the PE_PGRS domain containing subgroup and the PPE_MPTR domain containing subgroup [ 12 , 13 ]. It has been speculated that these proteins may play a role in virulence [ 14 ]. Pe/ppe genes are differentially expressed during infection [ 15 ] and some PE/PPE proteins have been shown to elicit immune responses by the host [ 14 , 16 ] and there is evidence that the PGRS domain can inhibit antigen processing [ 16 , 17 ].…”

Section: Introductionmentioning

confidence: 99%

Recombination in pe/ppe genes contributes to genetic variation in Mycobacterium tuberculosis lineages

et al. 2016

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BackgroundApproximately 10 % of the Mycobacterium tuberculosis genome is made up of two families of genes that are poorly characterized due to their high GC content and highly repetitive nature. The PE and PPE families are typified by their highly conserved N-terminal domains that incorporate proline-glutamate (PE) and proline-proline-glutamate (PPE) signature motifs. They are hypothesised to be important virulence factors involved with host-pathogen interactions, but their high genetic variability and complexity of analysis means they are typically disregarded in genome studies.ResultsTo elucidate the structure of these genes, 518 genomes from a diverse international collection of clinical isolates were de novo assembled. A further 21 reference M. tuberculosis complex genomes and long read sequence data were used to validate the approach. SNP analysis revealed that variation in the majority of the 168 pe/ppe genes studied was consistent with lineage. Several recombination hotspots were identified, notably pe_pgrs3 and pe_pgrs17. Evidence of positive selection was revealed in 65 pe/ppe genes, including epitopes potentially binding to major histocompatibility complex molecules.ConclusionsThis, the first comprehensive study of the pe and ppe genes, provides important insight into M. tuberculosis diversity and has significant implications for vaccine development.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-016-2467-y) contains supplementary material, which is available to authorized users.

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“…All PE proteins are characterized by a highly conserved N-terminal domain of ≅ 100 amino acids with the presence of a proline-glutamic acid (PE) motif at position 8–9 [ 4 ]. Out of the 99 PE genes found in Mtb H37Rv [ 4 ], 63 were annotated as PE_PGRS though some of these were pseudogenes or lacked some of the typical PE_PGRS features, so that only 51 PE_PGRS potentially functional proteins are expressed [ 8 ]. PE_PGRSs proteins share the same molecular architecture, characterized by the presence, beyond a PE domain, of i ) a typical PGRS domain varying in sequence and size containing a variable number of GGA-GGN repeats; ii ) a highly conserved putative transmembrane domain linking the PE and PGRS domains with a GRPLI motif around position 115; iii ) a unique C-terminal domain which is usually less than 30 amino acids long, but that in some cases (such as in PE_PGRS30) can be as large as 300 amino acids [ 7 , 11 , 12 ].…”

Section: Introductionmentioning

confidence: 99%

“…ulcerans and members of the Mtb complex), are scattered throughout the genome, and are differently regulated. The transcriptional regulation of some of them appears to be finely tuned depending on the environmental signals encountered during the complex steps of the infectious process, while others (as that encoding PE_PGRS33) are constitutively expressed [ 7 , 8 , 13 , 14 ]. The paucity of experimental data on PE_PGRSs has so far hampered a sufficient understanding of their role in TB pathogenesis.…”

Section: Introductionmentioning

confidence: 99%

PE_PGRS33 Contributes to Mycobacterium tuberculosis Entry in Macrophages through Interaction with TLR2

et al. 2016

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PE_PGRS represent a large family of proteins typical of pathogenic mycobacteria whose members are characterized by an N-terminal PE domain followed by a large Gly-Ala repeat-rich C-terminal domain. Despite the abundance of PE_PGRS-coding genes in the Mycobacterium tuberculosis (Mtb) genome their role and function in the biology and pathogenesis still remains elusive. In this study, we generated and characterized an Mtb H37Rv mutant (MtbΔ33) in which the structural gene of PE_PGRS33, a prototypical member of the protein family, was inactivated. We showed that this mutant entered macrophages with an efficiency up to ten times lower than parental or complemented strains, while its efficiency in infecting pneumocytes remained unaffected. Interestingly, the lack of PE_PGRS33 did not affect the intracellular growth of this mutant in macrophages. Using a series of functional deletion mutants of the PE_PGRS33 gene to complement the MtbΔ33 strain, we demonstrated that the PGRS domain is required to mediate cell entry into macrophages, with the key domain encompassing position 140–260 amino acids of PE_PGRS33. PE_PGRS33-mediated entry into macrophages was abolished in TLR2-deficient mice, as well as following treatment with wortmannin or an antibody against the complement receptor 3 (CR3), indicating that PE_PGRS33-mediated entry of Mtb in macrophages occurs through interaction with TLR2.

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The PE and PPE Protein Families ofMycobacterium tuberculosis

Cited by 18 publications

References 80 publications

PE_PGRS proteins ofMycobacterium tuberculosis: A specialized molecular task force at the forefront of host–pathogen interaction

PE_PGRS proteins ofMycobacterium tuberculosis: A specialized molecular task force at the forefront of host–pathogen interaction

Recombination in pe/ppe genes contributes to genetic variation in Mycobacterium tuberculosis lineages

PE_PGRS33 Contributes to Mycobacterium tuberculosis Entry in Macrophages through Interaction with TLR2

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