Structure and Function of the Mycobacterial Type VII Secretion Systems

Bunduc, Catalin M.; Bitter, Wilbert; Houben, Edith N.G.

doi:10.1146/annurev-micro-012420-081657

Cited by 33 publications

(38 citation statements)

References 118 publications

(258 reference statements)

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“…This could provide an explanation as to why dimeric ESX subcomplexes are more stable than their fully assembled counterparts 6,7 . The intermolecular EccB 5 -MycP 5 interactions (which have a surface area of around 395 Å 2 and ΔG = −0.1 kcal mol −1 ) are even more modest, which provides a rationale for why interactions between MycP 5 and the membrane complex have so far remained unknown.…”

Section: Periplasmic Mycp 5 -Eccb 5 Assemblymentioning

confidence: 99%

Structure and dynamics of a mycobacterial type VII secretion system

Bunduc

Fahrenkamp

Wald

et al. 2021

Nature

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Mycobacterium tuberculosis is the cause of one of the most important infectious diseases in humans, which leads to 1.4 million deaths every year1. Specialized protein transport systems—known as type VII secretion systems (T7SSs)—are central to the virulence of this pathogen, and are also crucial for nutrient and metabolite transport across the mycobacterial cell envelope2,3. Here we present the structure of an intact T7SS inner-membrane complex of M. tuberculosis. We show how the 2.32-MDa ESX-5 assembly, which contains 165 transmembrane helices, is restructured and stabilized as a trimer of dimers by the MycP5 protease. A trimer of MycP5 caps a central periplasmic dome-like chamber that is formed by three EccB5 dimers, with the proteolytic sites of MycP5 facing towards the cavity. This chamber suggests a central secretion and processing conduit. Complexes without MycP5 show disruption of the EccB5 periplasmic assembly and increased flexibility, which highlights the importance of MycP5 for complex integrity. Beneath the EccB5–MycP5 chamber, dimers of the EccC5 ATPase assemble into three bundles of four transmembrane helices each, which together seal the potential central secretion channel. Individual cytoplasmic EccC5 domains adopt two distinctive conformations that probably reflect different secretion states. Our work suggests a previously undescribed mechanism of protein transport and provides a structural scaffold to aid in the development of drugs against this major human pathogen.

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Section: Periplasmic Mycp 5 -Eccb 5 Assemblymentioning

confidence: 99%

Structure and dynamics of a mycobacterial type VII secretion system

Bunduc

Fahrenkamp

Wald

et al. 2021

Nature

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“…To date, 10 distinct protein secretion systems (named types I-X) have been identified [1][2][3]. While most of these are exclusive to Gram-negative bacteria, the type VII secretion system (T7SS) is encoded by many Grampositive Actinobacteria and Firmicutes [4,5]. The T7SS has been heavily studied in pathogenic mycobacteria, where it is essential for virulence [6][7][8].…”

Section: Introductionmentioning

confidence: 99%

Extreme genetic diversity in the type VII secretion system of Listeria monocytogenes suggests a role in bacterial antagonism

Bowran

Palmer

2021

Microbiology

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The type VII protein secretion system (T7SS) has been characterized in members of the phyla Actinobacteria and Firmicutes. In mycobacteria the T7SS is intimately linked with pathogenesis and intracellular survival, while in Firmicutes there is mounting evidence that the system plays a key role in interbacterial competition. A conserved membrane-bound ATPase protein, termed EssC in Staphylococcus aureus , is a critical component of the T7SS and is the primary receptor for substrate proteins. Genetic diversity in the essC gene of S. aureus has previously been reported, resulting in four protein variants that are linked to specific subsets of substrates. Here we have analysed the genetic diversity of the T7SS-encoding genes and substrate proteins across Listeria monocytogenes genome sequences. We find that there are seven EssC variants across the species that differ in their C-terminal region; each variant is correlated with a distinct subset of genes for likely substrate and accessory proteins. EssC1 is most common and is exclusively linked with polymorphic toxins harbouring a YeeF domain, whereas EssC5, EssC6 and EssC7 variants all code for an LXG domain protein adjacent to essC. Some essC1 variant strains encode an additional, truncated essC at their T7 gene cluster. The truncated EssC, comprising only the C-terminal half of the protein, matches the sequence of either EssC2, EssC3 or EssC4. In each case the truncated gene directly precedes a cluster of substrate/accessory protein genes acquired from the corresponding strain. Across L. monocytogenes strains we identified 40 LXG domain proteins, most of which are encoded at conserved genomic loci. These loci also harbour genes encoding immunity proteins and sometimes additional toxin fragments. Collectively our findings strongly suggest that the T7SS plays an important role in bacterial antagonism in this species.

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“…The core components of the inner-membrane part of T7SS have been identified (Pym et al , 2003). Nevertheless, it remains unknown whether the translocation of substrates through the inner and outer membrane is functionally coupled or not (one-or two-step, respectively), and if it deploys a specific outer-membrane complex to do so (Bunduc et al , 2020a). Proteins from the PE/PPE family, characterised by Pro-Glu and Pro-Pro-Glu motifs and secreted by T7SS, are often associated with the outer most layer of the mycobacterial cell envelope, and have been suggested to play a role in the membrane channel formation (Burggraaf et al , 2019; Cascioferro et al , 2007; Wang et al , 2020).…”

Section: Introductionmentioning

confidence: 99%

Priming mycobacterial ESX-secreted protein B to form a channel-like structure

Gijsbers

Vinciauskaite

Siroy

et al. 2021

Preprint

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ESX-1 is a major virulence factor of Mycobacterium tuberculosis, a secretion machinery directly involved in the survival of the microorganism from the immune system defence. It disrupts the phagosome membrane of the host cell through a contact-dependent mechanism. Recently, the structure of the inner-membrane core complex of the homologous ESX-3 and ESX-5 was resolved; however, the elements involved in the secretion through the outer membrane or those acting on the host cell membrane are unknown. Protein substrates might form this missing element. Here, we describe the oligomerisation process of the ESX-1 substrate EspB, which occurs upon cleavage of its C-terminal region and is favoured by an acidic environment. Cryo-electron microscopy data are presented which show that EspB from different mycobacterial species have a conserved quaternary structure, except for the non-pathogenic species M. smegmatis. EspB assembles into a channel with dimensions and characteristics suitable for the transit of ESX-1 substrates, as shown by the presence of another EspB trapped within. Our results provide insight into the structure and assembly of EspB, and suggests a possible function as a structural element of ESX-1.

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Structure and Function of the Mycobacterial Type VII Secretion Systems

Cited by 33 publications

References 118 publications

Structure and dynamics of a mycobacterial type VII secretion system

Structure and dynamics of a mycobacterial type VII secretion system

Extreme genetic diversity in the type VII secretion system of Listeria monocytogenes suggests a role in bacterial antagonism

Priming mycobacterial ESX-secreted protein B to form a channel-like structure

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