The PE16 (Rv1430) of Mycobacterium tuberculosis Is an Esterase Belonging to Serine Hydrolase Superfamily of Proteins

Sultana, Rafiya; Vemula, Mani Harika; Banerjee, Sharmishta; Guruprasad, Lalitha

doi:10.1371/journal.pone.0055320

Cited by 32 publications

(24 citation statements)

References 48 publications

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“…These secreted proteins are named after several highly conserved residues in their characteristic N‐terminal motifs: proline‐glutamic acid (PE) and proline‐proline‐glutamic acid (PPE) (Cole et al ., ). The C‐terminal domains of both PE and PPE proteins can be extremely long and some carry functional domains such as lipase (Deb et al ., ; Mishra et al ., ; Daleke et al ., ), aspartic protease (Barathy and Suguna, ) and serine hydrolase (Sultana et al ., 2011; 2013) domains. Although the precise function of these proteins is largely unknown, it has been demonstrated that various PE/PPE proteins are associated with virulence and persistence in the host (Sampson, ).…”

Section: Introductionmentioning

confidence: 99%

Structure of the Mycobacterium tuberculosis type VII secretion system chaperone EspG₅ in complex with PE25–PPE41 dimer

Korotkova

Freire

Phan

et al. 2014

Molecular Microbiology

135

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Summary The growth or virulence of Mycobacterium tuberculosis bacilli depends on homologous type VII secretion systems, ESX-1, ESX-3 and ESX-5, which export a number of protein effectors across membranes to the bacterial surface and environment. PE and PPE proteins represent two large families of highly polymorphic proteins that are secreted by these ESX systems. Recently, it was shown that these proteins require system-specific cytoplasmic chaperones for secretion. Here, we report the crystal structure of M. tuberculosis ESX-5-secreted PE25–PPE41 heterodimer in complex with the cytoplasmic chaperone EspG5. EspG5 represents a novel fold that is unrelated to previously characterized secretion chaperones. Functional analysis of the EspG5-binding region uncovered a hydrophobic patch on PPE41 that promotes dimer aggregation, and the chaperone effectively abolishes this process. We show that PPE41 contains a characteristic chaperone-binding sequence, the hh motif, which is highly conserved among ESX-1-, ESX-3- and ESX-5-specific PPE proteins. Disrupting the interaction between EspG5 and three different PPE target proteins by introducing different point mutations generally affected protein secretion. We further demonstrate that the EspG5 chaperone plays an important role in the ESX secretion mechanism by keeping aggregation-prone PE–PPE proteins in their soluble state.

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Section: Introductionmentioning

confidence: 99%

Structure of the Mycobacterium tuberculosis type VII secretion system chaperone EspG₅ in complex with PE25–PPE41 dimer

Korotkova

Freire

Phan

et al. 2014

Molecular Microbiology

135

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“…The majority of PE and PPE proteins contain relatively conserved N-terminal domains and C-terminal segments of variable length and sequence (Cole et al, 1998; Gey van Pittius et al, 2006). The function of PE and PPE C-terminal domains is largely unknown, although some of the PE and PPE proteins carry functional lipase and protease domains (Mishra et al, 2008; Daleke et al, 2011; Sultana et al, 2011; Sultana et al, 2013). The conserved structure of the PE–PPE N-terminal domains is important for PE–PPE heterodimer folding (Strong et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Structure of EspB, a secreted substrate of the ESX-1 secretion system of Mycobacterium tuberculosis

Korotkova

Piton

Wagner

et al. 2015

Journal of Structural Biology

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Mycobacterium tuberculosis secretes multiple virulence factors during infection via the general Sec and Tat pathways, and via specialized ESX secretion systems, also referred to as type VII secretion systems. The ESX-1 secretion system is an important virulence determinant because deletion of ESX-1 leads to attenuation of M. tuberculosis. ESX-1 secreted protein B (EspB) contains putative PE (Pro-Glu) and PPE (Pro-Pro-Glu) domains, and a C-terminal domain, which is processed by MycP1 protease during secretion. We determined the crystal structure of PE–PPE domains of EspB, which represents an all-helical, elongated molecule closely resembling the structure of the PE25–PPE41 heterodimer despite limited sequence similarity. Also, we determined the structure of full-length EspB, which does not have interpretable electron density for the C-terminal domain confirming that it is largely disordered. Comparative analysis of EspB in cell lysate and culture filtrates of M. tuberculosis revealed that mature secreted EspB forms oligomers. Electron microscopy analysis showed that the N-terminal fragment of EspB forms donut-shaped particles. These data provide a rationale for the future investigation of EspB's role in M. tuberculosis pathogenesis.

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“…Finally, a conserved serine hydrolase fold has been identified in several PE and PPE proteins (27). One of these proteins, PE16, has in vitro esterase activity against short-chain fatty acid esters (28). These observations suggest that some PE and PPE proteins have specific enzyme activities that could be important for M. tuberculosis metabolism and physiology.…”

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confidence: 99%

Mycobacterium tuberculosis Resists Stress by Regulating PE19 Expression

et al. 2016

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cMycobacterium tuberculosis requires the phosphate-sensing signal transduction system Pst/SenX3-RegX3 to resist host immune responses. A ⌬pstA1 mutant lacking a Pst phosphate uptake system component is hypersensitive to diverse stress conditions in vitro and is attenuated in vivo due to constitutive expression of the phosphate starvation-responsive RegX3 regulon. Transcriptional profiling of the ⌬pstA1 mutant revealed aberrant expression of certain pe and ppe genes. PE and PPE proteins, defined by conserved N-terminal domains containing Pro-Glu (PE) or Pro-Pro-Glu (PPE) motifs, account for a substantial fraction of the M. tuberculosis genome coding capacity, but their functions are largely uncharacterized. Because some PE and PPE proteins localize to the cell wall, we hypothesized that overexpression of these proteins sensitizes M. tuberculosis to stress by altering cell wall integrity. To test this idea, we deleted pe and ppe genes that were overexpressed by ⌬pstA1 bacteria. Deletion of a single pe gene, pe19, suppressed hypersensitivity of the ⌬pstA1 mutant to both detergent and reactive oxygen species. Ethidium bromide uptake assays revealed increased envelope permeability of the ⌬pstA1 mutant that was dependent on PE19. The replication defect of the ⌬pstA1 mutant in NOS2 ؊/؊ mice was partially reversed by deletion of pe19, suggesting that increased membrane permeability due to PE19 overexpression sensitizes M. tuberculosis to host immunity. Our data indicate that PE19, which comprises only a 99-amino-acid PE domain, has a unique role in the permeability of the M. tuberculosis envelope that is regulated to resist stresses encountered in the host. O ver 15 years ago, the novel PE and PPE protein families were identified in the complete genome sequence of Mycobacterium tuberculosis; together, these proteins represent over 7% of the genome coding capacity (1). Despite the attention placed on these protein families, their functions remain largely uncharacterized. PE and PPE proteins are defined by conserved N-terminal domains of ϳ110 or ϳ180 amino acids that contain Pro-Glu (PE) or Pro-Pro-Glu (PPE) sequence motifs, respectively (1). Although PE and PPE proteins can be identified in the genomes of all sequenced members of the Mycobacterium genus, their expansion into large multiprotein families is restricted to the slow-growing pathogenic mycobacterial species, including M. tuberculosis, and associated with the expansion of the ESX type VII secretion systems (2). There is evidence that some PE and PPE proteins are exported to the bacterial cell surface or extracellular milieu in an ESX-dependent manner (3-6). ESX-dependent export requires specific sequences within the PE or PPE domain (7, 8), including a recently described YxxxD/E ESX secretion targeting motif located near the C terminus of the ϳ110-amino-acid PE domain (9).The 99 PE proteins and 69 PPE proteins encoded by the M. tuberculosis H37Rv genome can be further divided into subfamilies based on C-terminal sequence motifs (2). The PE_PGRS (polymorphic GC-...

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The PE16 (Rv1430) of Mycobacterium tuberculosis Is an Esterase Belonging to Serine Hydrolase Superfamily of Proteins

Cited by 32 publications

References 48 publications

Structure of the Mycobacterium tuberculosis type VII secretion system chaperone EspG₅ in complex with PE25–PPE41 dimer

Structure of the Mycobacterium tuberculosis type VII secretion system chaperone EspG₅ in complex with PE25–PPE41 dimer

Structure of EspB, a secreted substrate of the ESX-1 secretion system of Mycobacterium tuberculosis

Mycobacterium tuberculosis Resists Stress by Regulating PE19 Expression

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The PE16 (Rv1430) of Mycobacterium tuberculosis Is an Esterase Belonging to Serine Hydrolase Superfamily of Proteins

Cited by 32 publications

References 48 publications

Structure of the Mycobacterium tuberculosis type VII secretion system chaperone EspG5 in complex with PE25–PPE41 dimer

Structure of the Mycobacterium tuberculosis type VII secretion system chaperone EspG5 in complex with PE25–PPE41 dimer

Structure of EspB, a secreted substrate of the ESX-1 secretion system of Mycobacterium tuberculosis

Mycobacterium tuberculosis Resists Stress by Regulating PE19 Expression

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Structure of the Mycobacterium tuberculosis type VII secretion system chaperone EspG₅ in complex with PE25–PPE41 dimer

Structure of the Mycobacterium tuberculosis type VII secretion system chaperone EspG₅ in complex with PE25–PPE41 dimer