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

Abstract

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.

PE_PGRS33, an Important Virulence Factor of Mycobacterium tuberculosis and Potential Target of Host Humoral Immune Response

“…PE and PPE protein families take their names from conserved motifs in their N-terminal regions [ 57 ]: specifically in residues 7–8 (proline–glutamic acid) for PE and 7–9 (proline–proline–glutamic acid) for PPE [ 56 ]. From almost 100 known representatives of the PE protein family [ 58 ], we can distinguish three subfamilies, including (i) the PE-only subfamily (< 100 aa in length), which is typically associated with a PPE protein to form a heterodimer; (ii) the PE_unique subfamily, which presents unique amino acid sequences of various length at the protein C-terminal side [ 59 ], such as the LipY triacylglycerol lipase, embedding an α/β hydrolase responsible for the hydrolysis of intracellular and extracellular triacylglycerol (TAG); (iii) the PE_PGRS subfamily, which contains numerous glycine-rich sequences (GGA-GGX repeats) [ 60 , 61 ]. Over 60% of the known PE proteins belong to the PE_PGRS subfamily [ 58 ].…”

“…This feature, also observed for the PE domains of PE/PPE complexes, suggests that either the PE domain of PE_PGRS33 forms homodimers or it is prone to interact with another protein to form a heterodimer. It is hitherto not clear whether PE_PGRS proteins require a protein partner [ 59 , 86 ], as in the case of PE/PPE proteins. Indeed, pe_pgrs genes are expressed as single operons.…”

“…Importantly, the PE domain of PE_PGRS33 is required for the protein translocation through the mycobacterial cell wall [ 63 , 82 , 88 , 90 , 91 ]. Once exerted this role, the PE domain is cleaved from the rest of the molecule, leaving the functional PGRS domain floating on the mycomembrane [ 59 ]. Therefore, it is tempting to surmise that some hydrolases may recognize PE_PGRS33 through its PE domain.…”

PE_PGRS: Vital proteins in promoting mycobacterial survival and modulating host immunity and metabolism

“…Recently, an increasing number of reports have shown that the mycobacterial PE_PGRS proteins play critical roles in bacterial pathogenesis and immune evasion (De Maio, Berisio, Manganelli, & Delogu, 2020; Meena, 2019). The PE_PGRS protein family, characterized by a special N‐terminal PE (Pro (P)‐Glu (E) motif) domain and a C‐terminal PGRS (Polymorphic GC‐rich Repetitive Sequences) domain, is restricted mainly to pathogenic mycobacteria, for example, M. tb , Mycobacterium bovis , Mycobacterium ulcerans , Mycobacterium marinum and Mycobacterium kansasii (Gey van Pittius et al, 2006; Tian & Jian‐Ping, 2010).…”

Host Cell Targets of Released Lipid and Secreted Protein Effectors of Mycobacterium tuberculosis

“…Furthermore, we also decided to limit the review to proteins that are secreted and released by Mtb which excludes many PE/PPE family proteins because they remain associated with the Mtb cell wall (e.g., . We point the reader to a current and exhaustive review on PE/PPE Mtb proteins (De Maio et al, 2020). In the absence of experimental data, we used SignalP 5.0 (Almagro Armenteros et al, 2019) to predict the presence of a signal peptide which indicates secretion via the SecA1/2 or Tat secretion systems.…”