New insights into the mycobacterial PE and PPE proteins provide a framework for future research

Summary

The PE and PPE proteins of Mycobacterium tuberculosis have been studied with great interest since their discovery. Named after the conserved proline (P) and glutamic acid (E) residues in their N‐terminal domains, these proteins are postulated to perform wide‐ranging roles in virulence and immune modulation. However, technical challenges in studying these proteins and their encoding genes have hampered the elucidation of molecular mechanisms and leave many open questions regarding the biological functions mediated by these proteins. Here, I review the shared and unique characteristics of PE and PPE proteins from a molecular perspective linking this information to their functions in mycobacterial virulence. I discuss how the different subgroups (PE_PGRS, PPE‐PPW, PPE‐SVP and PPE‐MPTR) are defined and why this classification of paramount importance to understand the PE and PPE proteins as individuals and or groups. The goal of this MicroReview is to summarize and structure the existing information on this gene family into a simplified framework of thinking about PE and PPE proteins and genes. Thereby, I hope to provide helpful starting points in studying these genes and proteins for researchers with different backgrounds. This has particular implications for the design and monitoring of novel vaccine candidates and in understanding the evolution of the M. tuberculosis complex.

Abstract

Structure of the EspG5‐PPE41‐PE25 complex (4KXR). The EspG chaperone (Gold) binds to the EspG‐binding domain of the PPE protein (Light blue), thereby conferring TypeVII secretion system specificity (Daleke et al., 2012b; Korotkova et al., 2014; Phan et al., 2017). The rest of the PPE‐protein interacts with its PE partner (Teal) via hydrophobic interactions. The conserved WxG residues of the PPE (Pink) and YxxxD/E of the PE (Red) are closely associated and may form a composite TypeVII secretion signal. The C‐terminus of the PPE (Green) extends toward the C‐terminus of the PE (Red), suggesting that PE/PPE protein pairs with C‐terminal extensions may have further PE/PPE interactions between those specific domains.