Structure of the mycobacterial ESX-5 type VII secretion system membrane complex by single-particle analysis
Open accessAbstract
Mycobacteria are characterized by their impermeable outer membrane, which is rich in mycolic acids 1. To transport substrates across this complex cell envelope, mycobacteria rely on type VII (also known as ESX) secretion systems 2. In Mycobacterium tuberculosis, these ESX systems are essential for growth and full virulence and therefore represent an attractive target for anti-tuberculosis drugs 3. However, the molecular details underlying type VII secretion are largely unknown, due to a lack of structural information. Here, we report the molecular architecture of the ESX-5 membrane complex from Mycobacterium xenopi determined at 13 Å resolution by electron microscopy. The four core proteins of the ESX-5 complex (EccB 5, EccC 5, EccD 5 and EccE 5) assemble with equimolar stoichiometry into an oligomeric assembly that displays six-fold symmetry. This membrane-associated complex seems to be embedded exclusively in the inner membrane, which indicates that additional components are required to translocate substrates across the mycobacterial outer membrane. Furthermore, the extended cytosolic domains of the EccC ATPase, which interact with secretion effectors, are highly flexible, suggesting an as yet unseen mode of substrate interaction. Comparison of our results with known structures of other bacterial secretion systems demonstrates that the architecture of type VII secretion system is fundamentally different, suggesting an alternative secretion mechanism.
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The ESX-5 nanomachine is integrated in the inner mycobacterial membrane and is composed of four proteins, EccB5, EccC5, EccD5, and EccE5, organized in a hexameric complex, as determined by cryo-electron microscopy and single-particle analysis.
“The ESX-5 nanomachine, which is integrated in the inner mycobacterial membrane, is composed of four proteins, namely, EccB5, EccC5, EccD5, and EccE5 (9, 10), that are organized in a hexameric complex, as recently determined by cryoelectron microscopy and single-particle analysis (10).”
From ESX/Type VII Secretion Systems—An Important Way Out for Mycobacterial Proteins (2019) · cites this paper as [10]
Another conserved ESX component is the serine protease MycP, although this protein is not directly integrated in the EccBCDE complex.
“Another conserved ESX component in mycobacterial ESX systems is the serine protease MycP, although this protein is not directly integrated in the EccBCDE complex (10,(41)(42)(43).”
From ESX/Type VII Secretion Systems—An Important Way Out for Mycobacterial Proteins (2019) · cites this paper as [10]
This organization of the ESX-5 nanomachine differs substantially from those of secretion systems of Gram-negative bacteria.
“This organization differs substantially from those of secretion systems of Gram-negative bacteria (10) (Fig. 2).”
From ESX/Type VII Secretion Systems—An Important Way Out for Mycobacterial Proteins (2019) · cites this paper as [10]
A certain flexibility of the cytosolic domains of EccC in interaction with effectors was suggested, which is different from the cognate ATPase in type IV secretion systems.
“A certain flexibility of the cytosolic domains of EccC in interaction with effectors was suggested (10,40), which is different from the cognate ATPase in type IV secretion systems (10).”
From ESX/Type VII Secretion Systems—An Important Way Out for Mycobacterial Proteins (2019) · cites this paper as [10]
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References 43 · Cited by 112
Research works printed but not linked: 7
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- Poulsen, C., Panjikar, S., Holton, S. J., Wilmanns, M. & Song, Y.-H. WXG100 protein superfamily consists of three subfamilies and exhibits an α-helical C-terminal conserved residue pattern. PLoS ONE 9, e89313 (2014).
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- Authors
- Beckham, K. S. H., Ciccarelli, L., Bunduc, C. M., Mertens, H. D. T., Ummels, R., Lugmayr, W., Mayr, J., Rettel, M., Savitski, M. M., Svergun, D. I., Bitter, W., Wilmanns, M., Marlovits, T. C., Parret, A. H. A., & Houben, E. N. G.
- Affiliations
- European Molecular Biology Laboratory (DE)
- Institute of Molecular Biotechnology (AT)
- Vrije Universiteit Amsterdam (NL)
- Amsterdam UMC Location Vrije Universiteit Amsterdam (NL)
- University Medical Center Hamburg-Eppendorf (DE)
- Corresponding author
- Marlovits, Thomas C.
- Parret, Annabel H. A.
- Houben, Edith N. G.
- ORCID
- Venue
- Nature Microbiology
- Published
- 2017-04-10
- Volume
- 2
- Issue
- 6
- Pages
- 17047-17047
- ISSN
- 2058-5276 (ISSN-L)
- OpenAlex
- W2607240190
- Cited by
- 112
- References
- 43
- Citations by year
- 2026: 7 · 2025: 3 · 2024: 4 · 2023: 9 · 2022: 10 · 2021: 18 · 2020: 17 · 2019: 17 · 2018: 20 · 2017: 7
- FWCI
- 12.84
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Nature Microbiology (publishedVersion)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (publishedVersion, other-oa)
- Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion)
- Desy publication database (The Deutsches Elektronen-Synchrotron) (submittedVersion)
- DESY (CERN, DESY, Fermilab, IHEP, and SLAC) (submittedVersion)
- VU Research Portal (submittedVersion, other-oa)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- DESY Publication Database (PUBDB) (Deutsches Elektronen-Synchrotron)
- Funders
- Nanyang Technological University
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek
- Deutsches Elektronen-Synchrotron
- Topics
- Health Sciences › Medicine › Infectious Diseases › Tuberculosis Research and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Bacterial Genetics and Biotechnology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Structural Biology › Advanced Electron Microscopy Techniques and Applications
- Keywords
- type VII secretion system, Mycobacterium xenopi, Mycobacterium tuberculosis, inner membrane, secretion mechanism, tuberculosis drug targets
- MeSH terms
- Type VII Secretion Systems, Adenosine Triphosphatases, Antigens, Bacterial, Bacterial Proteins, Cell Membrane, Cell Wall, Mycobacterium tuberculosis, Electron Microscope Tomography
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