Specific Chaperones for the Type VII Protein Secretion Pathway

Daleke, Maria H.; Woude, Aniek D. van der; Parret, Annabel; Ummels, Roy; Groot, Anne Marit de; Watson, David E.; Piersma, Sander R.; Jiménez, Connie R.; Luirink, Joen; Bitter, Wilbert; Houben, Edith N.G.

doi:10.1074/jbc.m112.397596

Cited by 82 publications

(112 citation statements)

References 30 publications

(73 reference statements)

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“…In contrast to PE and PPE proteins, which are translocated through the ESX, EspG is not secreted (22). In light of the nanomolar K d between PPE protein and EspG, this observation raises questions about how the PE-PPE dimer is released from the complex for secretion.…”

Section: Espg Encoded In the Esx-5 Gene Cluster Of Mtb Interacts Exclmentioning

confidence: 78%

“…However, our results suggest that some cross-talk may occur between clusters. For example, PPE68 is encoded within the ESX-1 locus in Mtb and Mycobacterium marinum, and it was previously shown to interact with EspG 1 from the same cluster (22). However, the PPE68-like chimera also binds to EspG 5Mt with high affinity (Figs.…”

Section: Espg Encoded In the Esx-5 Gene Cluster Of Mtb Interacts Exclmentioning

confidence: 99%

“…EccA is an ATPase that may be involved in dissociating the EspG-PPE interaction because (i) EccA proteins are only encoded in ESX gene clusters that also encode PE and PPE proteins, (ii) EccA mutants accumulate PPE-bound EspG (22), and (iii) EccA interacts with both PPE protein (35) and EspG (SI Appendix, Fig. S12) in yeast two-hybrid assays.…”

Section: Espg Encoded In the Esx-5 Gene Cluster Of Mtb Interacts Exclmentioning

confidence: 99%

“…EspG has been reported to interact with PPE proteins and is required for PE-PPE secretion (22,26). To understand how EspG recognizes specific PE-PPE complexes and mediates their secretion through the ESX, we determined the crystal structure of a ternary complex of the EspG encoded in the ESX-5 gene cluster of Mtb (EspG 5Mt ) bound to the PE25-PPE41 dimer at a resolution of 2.45 Å (SI Appendix, Fig.…”

Section: Espg Encoded In the Esx-5 Gene Cluster Of Mtb Interacts Exclmentioning

confidence: 99%

“…This structure reveals how each of the four EspGs in Mtb interacts with a different subset of the ∼100 PE and ∼70 PPE proteins, directing specific classes of PE-PPE "effector" proteins through separate secretory pathways. ESX secretion-associated protein G (EspG) (22), another ESXencoded protein of unknown structure and function. However, the molecular basis for this interaction and its functional importance in PPE secretion remain unclear.…”

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confidence: 99%

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Structure of a PE–PPE–EspG complex fromMycobacterium tuberculosisreveals molecular specificity of ESX protein secretion

Ekiert

Cox

2014

Proc. Natl. Acad. Sci. U.S.A.

102

131

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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.tuberculosis | protein secretion | antigenic variation | virulence factor | host-pathogen interactions

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Section: Espg Encoded In the Esx-5 Gene Cluster Of Mtb Interacts Exclmentioning

confidence: 78%

Section: Espg Encoded In the Esx-5 Gene Cluster Of Mtb Interacts Exclmentioning

confidence: 99%