https://orcid.org/0000-0002-4744-9820
Figures & data
Figure 1. Schematic representation of the evolution of pe/ppe genes in the Mycobacterium tuberculosis complex (MTBC).
pe/ppe genes first emerged in the mycobacterial genome in the esx-1 locus and evolved following a series of duplication events in the homologous esx loci and then spread in the genome as single genes or paired. The combination of duplication and intragenomic recombination events led to the amplification of pe and ppe genes and the emergence of the ppe_mptr and pe_pgrs genes, characterized by the presence of repetitive motifs. Based on the features of the PGRS domain and the downstream C-terminal domain, PE_PGRS proteins can be further subdivided in three group (A, B, and C) [Citation16].
Figure 2. Domain organization of PE_PGRS proteins and hydrophobicity score of PE domains.
Schematic showing the typical domain organization of PE_PGRS proteins (A). Hydrophobicity scores, as assessed by ProtScale Expasy Tool with Kyte and Doolitlle scale, of the PE domain of: PE proteins belonging to the PE/PPE subfamily (B); PE-unique proteins (C); PE_PGRS proteins (D). Panel E shows the hydrophobicity scores for three selected PE proteins belonging to three different subfamilies: PE25 of the PE/PPE pairs; LipY of PE-unique and PE_PGRS33 of the PE_PGRS subfamily. Panel F: cartoon representation of the homology model of the PE domain of PE_PGRS30 in two orthogonal orientations. The model (including residues 8–84) was obtained using MODELER [Citation38]. Hydrophobic and aromatic residues are shown in orange ball-and-stick representation.
Figure 3. A PGII sandwich domain of PE_PGRS30.
Ball-and-stick and cartoon model of a the PGII sandwich domain of PE_PGRS30, embedded between amino acid residues 512 and 586. Panels A and B show two perpendicular views. C) amino acidic sequence of the PGRS domain of PE_PGRS30 and highlighted in blue the sequence corresponding to PGII shown in A and B.
Figure 4. Schematic representation of the PE_PGRS localization in the mycobacterial cell wall.
The picture shows the hypothetical model, inferred from the experimental results gathered so far, on the localization of PE_PGRS proteins on the mycobacterial outer membrane. The model highlights the putative role of the PGII sandwich domains (green) aligned orthogonally to the mycomembrane and the unique amino acids residues residing in the loops connecting the PGII helices (violet). The unique C-terminal domain found downstream of the PGRS domain is shown in blue.
Table 1. Schematic summary of the PE_PGRS proteins functional activities during Mtb pathogenesis.
Figure 5. Schematic representation of the pathogenetic processes at cellular level involving PE_PGRS proteins during Mtb pathogenesis.
The figure identifies the extracellular and intracellular steps in Mtb pathogenesis for which the involvement of a PE_PGRS proteins has been demonstrated. The number close to the bacilli (shown in red) correspond to the PE_PGRS (for example, 33 indicates interaction of PE_PGRS with TLR2).
Figure 6. Role of PE_PGRS proteins in TB pathogenesis.
(a) Mutation of some pe_pgrs genes induce a clear phenotype during the chronic persistent steps of the infectious process. The experimental conditions and animal models of infection used in these experiments are reported on the right side of the panel. (b) Schematic with the key steps in the natural history of TB in immunocompetent humans. PE_PGRS proteins play a key role in steps 2 and 3, when the interplay between Mtb and the complex immune system of mammals occurs.
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