Sandbox Reserved 1075

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.

EspG5 protein

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.

Residue Hinderance

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.

Electrostatics

Pocket Residues

Jon

Structural highlights

This is a sample scene created with SAT to by Group, and another to make of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.

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.