Structural Insight into How Bacteria Prevent Interference between Multiple Divergent Type IV Secretion Systems
Open accessAbstract
Prokaryotes use type IV secretion systems (T4SSs) to translocate substrates (e.g., nucleoprotein, DNA, and protein) and/or elaborate surface structures (i.e., pili or adhesins). Bacterial genomes may encode multiple T4SSs, e.g., there are three functionally divergent T4SSs in some Bartonella species ( vir , vbh , and trw ). In a unique case, most rickettsial species encode a T4SS ( rvh ) enriched with gene duplication. Within single genomes, the evolutionary and functional implications of cross-system interchangeability of analogous T4SS protein components remains poorly understood. To lend insight into cross-system interchangeability, we analyzed the VirB8 family of T4SS channel proteins. Crystal structures of three VirB8 and two TrwG Bartonella proteins revealed highly conserved C-terminal periplasmic domain folds and dimerization interfaces, despite tremendous sequence divergence. This implies remarkable structural constraints for VirB8 components in the assembly of a functional T4SS. VirB8/TrwG heterodimers, determined via bacterial two-hybrid assays and molecular modeling, indicate that differential expression of trw and vir systems is the likely barrier to VirB8-TrwG interchangeability. We also determined the crystal structure of Rickettsia typhi RvhB8-II and modeled its coexpressed divergent paralog RvhB8-I. Remarkably, while RvhB8-I dimerizes and is structurally similar to other VirB8 proteins, the RvhB8-II dimer interface deviates substantially from other VirB8 structures, potentially preventing RvhB8-I/RvhB8-II heterodimerization. For the rvh T4SS, the evolution of divergent VirB8 paralogs implies a functional diversification that is unknown in other T4SSs. Collectively, our data identify two different constraints (spatiotemporal for Bartonella trw and vir T4SSs and structural for rvh T4SSs) that mediate the functionality of multiple divergent T4SSs within a single bacterium. IMPORTANCE Assembly of multiprotein complexes at the right time and at the right cellular location is a fundamentally important task for any organism. In this respect, bacteria that express multiple analogous type IV secretion systems (T4SSs), each composed of around 12 different components, face an overwhelming complexity. Our work here presents the first structural investigation on factors regulating the maintenance of multiple T4SSs within a single bacterium. The structural data imply that the T4SS-expressing bacteria rely on two strategies to prevent cross-system interchangeability: (i) tight temporal regulation of expression or (ii) rapid diversification of the T4SS components. T4SSs are ideal drug targets provided that no analogous counterparts are known from eukaryotes. Drugs targeting the barriers to cross-system interchangeability (i.e., regulators) could dysregulate the structural and functional independence of discrete systems, potentially creating interference that prevents their efficient coordination throughout bacterial infection.
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VirB8 is part of the type IV secretion system of R. typhi, the causative agent of murine typhus.
“We also designed binders to the prokaryotic pathogen protein VirB8, part of the type IV secretion system of R. typhi, the causative agent of murine typhus26.”
From Design of protein-binding proteins from the target structure alone (2022) · cites this paper as [26]
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1 of the 91 references couldn’t be matched to a known paper.
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Design of protein-binding proteins from the target structure alone
Cao, L., Coventry, B., Goreshnik, I., Huang, B., Sheffler, W., Park, J. S., Jude, K. M., Marković, I., Kadam, R. U., Verschueren, K. H. G., et al. (2022) · Nature · doi:10.1038/s41586-022-04654-9 · Cited by 577 · see citing works
Bacteria-Killing Type IV Secretion Systems
Sgro, G. G., Oka, G. U., de Souza, D. P., Cenens, W., Bayer‐Santos, E., Matsuyama, B. Y., Bueno, N. F., dos Santos, T. R., Alvarez‐Martinez, C. E., Salinas, R. K., et al. (2019) · Frontiers in Microbiology · doi:10.3389/fmicb.2019.01078 · Cited by 156 · see citing works
Nourdin, G., Sánchez, P., Molina, C. F., Espinoza-Rojas, D. A., Oliver, C., Ruíz, P., Vargas‐Chacoff, L., Cárcamo, J. G., Figueroa, J. E., Mancilla, M., et al. (2017) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2017.00459 · Cited by 68 · see citing works
Carraro, N., Durand, R., Rivard, N., Anquetil, C., Barrette, C., Humbert, M., & Burrus, V. (2017) · PLoS Genetics · doi:10.1371/journal.pgen.1006705 · Cited by 58 · see citing works
The evolutionary origin of host association in the Rickettsiales
Schön, M. E., Martijn, J., Vosseberg, J., Köstlbacher, S., & Ettema, T. J. G. (2022) · Nature Microbiology · doi:10.1038/s41564-022-01169-x · Cited by 56 · see citing works
TheRickettsiatype IV secretion system: unrealized complexity mired by gene family expansion
Gillespie, J. J., Phan, I. Q., Driscoll, T., Guillotte, M. L., Lehman, S. S., Rennoll-Bankert, K. E., Subramanian, S., Beier‐Sexton, M., Myler, P. J., Rahman, M. S., et al. (2016) · Pathogens and Disease · doi:10.1093/femspd/ftw058 · Cited by 54 · see citing works
Self-citationMolecular Mechanisms of Bartonella and Mammalian Erythrocyte Interactions: A Review
Deng, H., Pang, Q., Zhao, B., & Vayssier‐Taussat, M. (2018) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2018.00431 · Cited by 48 · see citing works
Role and Function of the Type IV Secretion System in Anaplasma and Ehrlichia Species
Rikihisa, Y. (2017) · Current topics in microbiology and immunology · doi:10.1007/978-3-319-75241-9_12 · Cited by 44 · see citing works
Structural Analysis and Inhibition of TraE from the pKM101 Type IV Secretion System
Casu, B., Smart, J., Hancock, M. A., Smith, M. A., SYGUSCH, J., & Baron, C. (2016) · Journal of Biological Chemistry · doi:10.1074/jbc.m116.753327 · Cited by 40 · see citing works
Small Regulatory RNAs of Rickettsia conorii
Narra, H. P., Schroeder, C. L. C., Sahni, A., Rojas, M., Khanipov, K., Fofanov, Y., & Sahni, S. K. (2016) · Scientific Reports · doi:10.1038/srep36728 · Cited by 29 · see citing works
Protein Dynamics in F-like Bacterial Conjugation
Bragagnolo, N., Rodriguez, C., Samari-Kermani, N., Fours, A., Korouzhdehi, M., Lysenko, R., & Audette, G. F. (2020) · Biomedicines · doi:10.3390/biomedicines8090362 · Cited by 28 · see citing works
Giengkam, S., Kullapanich, C., Wongsantichon, J., Adcox, H. E., Gillespie, J. J., & Salje, J. (2023) · mSphere · doi:10.1128/msphere.00268-23 · Cited by 28 · see citing works
Self-citationCasu, B., Arya, T., Bessette, B., & Baron, C. (2017) · Scientific Reports · doi:10.1038/s41598-017-14953-1 · Cited by 27 · see citing works
Casu, B., Mary, C., Sverzhinsky, A., Fouillen, A., Nanci, A., & Baron, C. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1802501115 · Cited by 16 · see citing works
Structural and Molecular Biology of Type IV Secretion Systems
Bergé, C., Waksman, G., & Terradot, L. (2017) · Current topics in microbiology and immunology · doi:10.1007/978-3-319-75241-9_2 · Cited by 15 · see citing works
Protein interactions within and between two F‐type type IV secretion systems
Koch, B., Callaghan, M. M., Tellechea‐Luzardo, J., Seeger, A. Y., Dillard, J. P., & Krasnogor, N. (2020) · Molecular Microbiology · doi:10.1111/mmi.14582 · Cited by 15 · see citing works
Metagenome diversity illuminates the origins of pathogen effectors
Lehman, S. S., Verhoeve, V. I., Driscoll, T., Beckmann, J. F., & Gillespie, J. J. (2024) · mBio · doi:10.1128/mbio.00759-23 · Cited by 16 · see citing works
Self-citationChen, J. Z., Gall, B., Pulsford, S. B., Tokuriki, N., & Jackson, C. J. (2025) · Molecular biology and evolution · doi:10.1093/molbev/msaf136 · Cited by 8 · see citing works
Improved algorithms for quantifying the near symmetry of proteins: complete side chains analysis
Tuvi‐Arad, I., & Alon, G. (2019) · Journal of Cheminformatics · doi:10.1186/s13321-019-0360-9 · Cited by 12 · see citing works
Robust de novo design of protein binding proteins from target structural information alonePreprint
Cao, L., Coventry, B., Goreshnik, I., Huang, B., Park, J. S., Jude, K. M., Marković, I., Kadam, R. U., Verschueren, K. H. G., Verstraete, K., et al. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.09.04.459002 · Cited by 12 · see citing works
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Evaluation of changes to the Rickettsia rickettsii transcriptome during mammalian infection
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Leitner, M., Bishop, C., & Sassan Asgari, B. (2021) · mSphere · doi:10.1128/msphere.00433-21 · Cited by 9 · see citing works
The type IV secretion system core component VirB8 interacts via the β1‐strand with VirB10
Sharifahmadian, M., Nlend, I. U., Lecoq, L., Omichinski, J. G., & Baron, C. (2017) · FEBS Letters · doi:10.1002/1873-3468.12770 · Cited by 9 · see citing works
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Molecular architecture of the Legionella Dot/Icm type IV secretion systemPreprint
Ghosal, D., Chang, Y., Jeong, K. C., Vogel, J. P., & Jensen, G. J. (2018) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/312009 · Cited by 7 · see citing works
Advances in the Assembly Model of Bacterial Type IVB Secretion Systems
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Metagenome diversity illuminates origins of pathogen effectorsPreprint
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Self-citationType IV Secretion in Agrobacterium tumefaciens and Development of Specific Inhibitors
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Conformational changes of baseplate regulating tail contraction of Staphylococcus phage 812Preprint
Bíňovský, J., Šiborová, M., Zlatohurska, M., Nováček, J., Bárdy, P., Baška, R., Škubník, K., Botka, T., Benešík, M., Pantůček, R., et al. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.09.19.613683 · Cited by 5 · see citing works
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Conformational changes of the baseplate regulating tail contraction of Staphylococcus phage 812
Bíňovský, J., Šiborová, M., Zlatohurska, M., Nováček, J., Bárdy, P., Baška, R., Škubník, K., Botka, T., Benešík, M., Pantůček, R., et al. (2026) · The EMBO Journal · doi:10.1038/s44318-026-00834-9
- Authors
- Gillespie, J. J., Phan, I. Q. H., Scheib, H., Subramanian, S., Edwards, T. E., Lehman, S. S., Piitulainen, H., Sayeedur Rahman, M., Rennoll-Bankert, K. E., Staker, B. L., Taira, S., Stacy, R., Myler, P. J., Azad, A. F., & Pulliainen, A. T.
- Affiliations
- University of Maryland, Baltimore (US)
- Center for Infectious Disease Research (US)
- The University of Queensland (AU)
- Beryllium (United States) (US)
- University of Helsinki (FI)
- Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland, USA
- Corresponding author
- Gillespie, Joseph J.
- Pulliainen, Arto T.
- ORCID
- Venue
- mBio
- Publisher
- American Society for Microbiology
- Published
- 2015-12-31
- Volume
- 6
- Issue
- 6
- Pages
- e01867-15
- ISSN
- 2150-7511 (ISSN-L)
- 2161-2129
- PMC
- PMC4676284
- OpenAlex
- W2194597461
- Cited by
- 36
- References
- 91
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 2 · 2023: 3 · 2022: 5 · 2021: 2 · 2020: 2 · 2019: 2 · 2018: 5 · 2017: 9 · 2016: 3
- FWCI
- 3.90
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- mBio (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Työväentutkimus Vuosikirja (submittedVersion)
- Funders
- University of Washington
- Sigrid Juséliuksen Säätiö
- National Institutes of Health
- U.S. Public Health Service (HHSN272200700057C., HHSN272201200025C)
- National Institute of Allergy and Infectious Diseases (HHSN272200700057 C, T32AI007540, R01AI017828, R01AI59118, HHSN272201200025C, R01AI059118, R01AI043006, T32AI095190)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Bacterial Genetics and Biotechnology
- Life Sciences › Immunology and Microbiology › Parasitology › Bartonella species infections research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Structural Characterization
- Keywords
- type IV secretion system, VirB8, Bartonella, Rickettsia typhi, heterodimerization, periplasmic domain, gene duplication, functional diversification, bacterial virulence, crystal structure, molecular modeling, two-hybrid assay
- MeSH terms
- Type IV Secretion Systems, Bartonella, Models, Molecular, Protein Binding, Protein Conformation, Rickettsia typhi, Substrate Specificity, Crystallography, X-Ray, Two-Hybrid System Techniques, Protein Multimerization
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
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