EspG is a key secretion protein involved with the virulence of mycobacterium tuberculosis. The specificity of EspG binding affinity to its specific PE-PPE ligand has many contributing factors. The four different EspG proteins found in mycobacterium tuberculosis have different characteristics that influence binding, where EspG5 binds to the most PE-PPE proteins. Here EspG PE-PPE complex is to be excreted in the ESAT-6 pathway.
Function
Through specific binding factors, an EspG binds to its PE-PPE ligand to be secreted through the ESAT pathway. This places
Excretion
EspG PE-PPE excretion is done through the ESX secretion pathway.
Binding
The EspG-PE-PPE binding is highly specific. The variety of binding factors influence the EspG that PE-PPE will bind to. The secretion pathway carried out needs the coupled protein.
Residue Interactions:
The residues on the random turn in the PE-PPE protein are key for the specificity to the EspG protein. Coils between PE-PPE proteins vary greatly and influence binding affinity. Combined with its β-2 & β-3 interactions on the EspG protein, the EspG protein is PE-PPE specific. These make up the bulk of residue interactions in the complex.
Concavity:
Electrostatics:
There is an overall negative charge on the PE-PPE complex, and the binding tip is only partially negative. On the EspG5 protein, the binding pocket is partially positive, which aids coupling of the EspG & PE-PPE complex. The other EspG proteins found in 'mycobacterium tuberculosis' have different electrostatic pocket charges which prevent binding of the PE25-PPE41 ligand.
Pocket Residues
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Structural highlights
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Relevance
Publication Abstract from PubMed
Nearly 10% of the coding capacity of the Mycobacterium tuberculosis genome is devoted to two highly expanded and enigmatic protein families called PE and PPE, some of which are important virulence/immunogenicity factors and are secreted during infection via a unique alternative secretory system termed "type VII." How PE-PPE proteins function during infection and how they are translocated to the bacterial surface through the five distinct type VII secretion systems [ESAT-6 secretion system (ESX)] of M. tuberculosis is poorly understood. Here, we report the crystal structure of a PE-PPE heterodimer bound to ESX secretion-associated protein G (EspG), which adopts a novel fold. This PE-PPE-EspG complex, along with structures of two additional EspGs, suggests that EspG acts as an adaptor that recognizes specific PE-PPE protein complexes via extensive interactions with PPE domains, and delivers them to ESX machinery for secretion. Surprisingly, secretion of most PE-PPE proteins in M. tuberculosis is likely mediated by EspG from the ESX-5 system, underscoring the importance of ESX-5 in mycobacterial pathogenesis. Moreover, our results indicate that PE-PPE domains function as cis-acting targeting sequences that are read out by EspGs, revealing the molecular specificity for secretion through distinct ESX pathways.
Structure of a PE-PPE-EspG complex from Mycobacterium tuberculosis reveals molecular specificity of ESX protein secretion.,Ekiert DC, Cox JS Proc Natl Acad Sci U S A. 2014 Oct 14;111(41):14758-63. doi:, 10.1073/pnas.1409345111. Epub 2014 Oct 1. PMID:25275011[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
