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Structural and functional diversity of type IV secretion systems

Nature Reviews Microbiology volume 22, pages 170–185 (2024)Cite this article

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Abstract

Considerable progress has been made in recent years in the structural and molecular biology of type IV secretion systems in Gram-negative bacteria. The latest advances have substantially improved our understanding of the mechanisms underlying the recruitment and delivery of DNA and protein substrates to the extracellular environment or target cells. In this Review, we aim to summarize these exciting structural and molecular biology findings and to discuss their functional implications for substrate recognition, recruitment and translocation, as well as the biogenesis of extracellular pili. We also describe adaptations necessary for deploying a breadth of processes, such as bacterial survival, host–pathogen interactions and biotic and abiotic adhesion. We highlight the functional and structural diversity that allows this extremely versatile secretion superfamily to function under different environmental conditions and in different bacterial species. Additionally, we emphasize the importance of further understanding the mechanism of type IV secretion, which will support us in combating antimicrobial resistance and treating type IV secretion system-related infections.

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Fig. 1: The functional versatility of type IV secretion systems.
Fig. 2: Structure of minimal type IV secretion system and pilus biogenesis mechanism model.
Fig. 3: Structural organization of expanded type IV secretion system.
Fig. 4: Examples of type IV secretion system subunit adaptations for functional diversification.
Fig. 5: Structure of VirD4-like and VirB11-like ATPases.
Fig. 6: Models for substrate recruitment and transport through the type IV secretion system.
Fig. 7: Structure comparison between minimal, expanded and archaea pilus.

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Acknowledgements

Work in the laboratories of authors was supported by the Welcome Trust grants 215164/Z/18/Z and 217089/Z/19/Z to T.R.D.C. and G.W., respectively, and by the National Institutes of Health grants NIH 1R35GM131892 and NIH 1R21AI159970 to P.J.C.

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Authors and Affiliations

  1. Centre for Bacterial Resistance Biology, Department of Life Sciences, Imperial College, London, UK

    Tiago R. D. Costa & Jonasz B. Patkowski

  2. Institute of Structural and Molecular Biology, Birkbeck and UCL, London, UK

    Kévin Macé & Gabriel Waksman

  3. Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes and CNRS, Rennes, France

    Kévin Macé

  4. Department of Microbiology and Molecular Genetics, McGovern Medical School at UTHealth, Houston, TX, USA

    Peter J. Christie

Authors
  1. Tiago R. D. Costa
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  2. Jonasz B. Patkowski
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  3. Kévin Macé
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  4. Peter J. Christie
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  5. Gabriel Waksman
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Contributions

T.R.D.C., J.B.P. and P.J.C. wrote the article. T.R.D.C., J.B.P., P.J.C. and K.M. researched data for the article. K.M. made the figures and supplementary table with contributions from T.R.D.C. and J.B.P. All authors reviewed and/or edited the manuscript before submission.

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Correspondence to Tiago R. D. Costa, Peter J. Christie or Gabriel Waksman.

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Glossary

Adhesins

Proteins found on the surface of cells that facilitate attachment to other biotic or abiotic surfaces.

Biofilm

An assemblage of bacteria on a biotic or abiotic surface, often with a defined architecture, that is embedded in an extracellular matrix typically composed of proteins, DNA, lipids and other biological molecules.

Biotic and abiotic adhesion

The attachment of microorganisms to living (biotic) or non-living (abiotic) surfaces, a process that typically facilitates biofilm formation, niche establishment or infection.

Co-evolution

The reciprocal influence and evolution patterns between two proteins that interact or are dependent on each other for function, and have evolved in a coordinated, nonrandom manner reflecting their mutual adaptation over time.

Conjugation

A type of horizontal gene transfer in bacteria where genetic material, such as plasmids containing genes for antibiotic resistance, is transferred from a donor bacterium to a recipient bacterium.

Conjugative pili

Helical hair-like appendages formed by protein–phospholipid complexes that assemble on the surface of bacteria and can act as conduits for DNA transfer between donor and recipient bacteria.

Conjugative plasmid

A type of a bacterial plasmid that encodes a conjugative machinery, through which the plasmid and its cargoes of antimicrobial resistance genes, virulence factors or other fitness traits are delivered between bacterial cells.

Correlative light and electron microscopy

(CLEM). Imaging technique that combines fluorescence microscopy and electron microscopy to correlate high-resolution structural information with specific molecular or cellular labelling in the same sample.

Crosslinking

Artificial formation of covalent bonds by a crosslinker between different molecules that interact or co-localize within a biological sample, with the common application of studying protein–protein or protein–ligand interactions.

Cryo-electron microscopy

(cryo-EM). Electron microscopy imaging technique that involves freezing samples in vitreous ice to preserve their native state and is used to visualize the three-dimensional structure of biological molecules and complexes at near-atomic resolution.

Cryo-electron tomography

(cryo-ET). Specialized variation of cryo-electron microscopy that enables the visualization of large cellular components or organelles within their cellular environment.

Cryo-focused ion beam

(cryo-FIB). A technique used to prepare samples for cryo-electron microscopy by thinning frozen samples with a focused ion beam, leading to an improved signal-to-noise ratio and resolution in the imaging of biological samples.

Effector

Bacterial protein, often secreted through a dedicated secretion system, that interacts with and manipulates cellular processes within a host organism, promoting bacterial survival, colonization or infection.

Nanobodies

Single-domain antibody fragments derived from heavy-chain-only IgG antibodies that are naturally found in the Camelidae family, which includes camels, llamas and alpacas.

Polytopic topology

Protein structure that contains multiple transmembrane segments embedded in the cell membrane.

Relaxosome

A complex of proteins responsible for specific nicking of the double-stranded DNA, unwinding of DNA strands and delivering the single-stranded DNA transfer intermediate to the type IV secretion apparatus before conjugation.

Rotational raise

Angle at which adjacent rings stack in helical assemblies, influencing the overall helical symmetry and packing of the structure.

Site-directed mutagenesis

Molecular biology technique used to introduce specific nucleotide mutations into DNA sequences, with the purpose of studying their effects on protein structure and function.

Toll-like receptor

A family of pattern recognition receptors in the immune system that specifically recognize conserved patterns in pathogens and trigger an immune response.

Translocation signals

Specific amino acid sequences that confer recognition of a protein as a substrate for a dedicated transport machinery for delivery to a specific cellular location, the extracellular milieu or another bacterial or eukaryotic cell.

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Costa, T.R.D., Patkowski, J.B., Macé, K. et al. Structural and functional diversity of type IV secretion systems. Nat Rev Microbiol 22, 170–185 (2024). https://doi.org/10.1038/s41579-023-00974-3

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