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  • Review Article
  • Published:

Secretion systems in Gram-negative bacteria: structural and mechanistic insights

Nature Reviews Microbiology volume 13, pages 343–359 (2015)Cite this article

Subjects

Key Points

  • Gram-negative bacteria have evolved a wide array of secretion systems to transport small molecules, proteins and DNA into the extracellular space or target cells. In this Review, we describe insights into the structural and mechanistic features of the six secretion systems (types I–VI) of Gram-negative bacteria, the unique mycobacterial type VII secretion system, the chaperone–usher pathway and the curli biogenesis machinery.

  • These systems are remarkably varied in size, composition and architecture. Double-membrane-spanning secretion systems are composed of many tens of protein subunits and can reach multi-megadalton sizes, whereas outer-membrane-spanning systems are relatively simple and are usually composed of only one type of subunit.

  • These systems can transport folded or unfolded substrates and use various energy sources to power transport, from ATP to proton or entropy gradients.

  • Recent structural and molecular advances have uncovered remarkable structural and functional similarities between secretion systems that have the potential to be exploited for the development of novel antibacterial compounds.

Abstract

Bacteria have evolved a remarkable array of sophisticated nanomachines to export various virulence factors across the bacterial cell envelope. In recent years, considerable progress has been made towards elucidating the structural and molecular mechanisms of the six secretion systems (types I–VI) of Gram-negative bacteria, the unique mycobacterial type VII secretion system, the chaperone–usher pathway and the curli secretion machinery. These advances have greatly enhanced our understanding of the complex mechanisms that these macromolecular structures use to deliver proteins and DNA into the extracellular environment or into target cells. In this Review, we explore the structural and mechanistic relationships between these single- and double-membrane-embedded systems, and we briefly discuss how this knowledge can be exploited for the development of new antimicrobial strategies.

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Figure 1: Structural organization of the secretion systems that span the double membrane of Gram-negative bacteria.
Figure 2: Structural organization of the secretion systems that span the outer membrane of Gram-negative bacteria.
Figure 3: Models for the mechanism of substrate secretion in Gram-negative bacteria.
Figure 4: Timeline of the discovery of Gram-negative bacterial secretion systems and some of the main structural achievements in the field.

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Acknowledgements

The authors thank T. Marlovits for providing an EM map with a longer T3SS needle and W. G. J. Hol for the constructed dodecameric ring of the GspD cytoplasmic domains. This work was funded by Wellcome Trust grant 098302 and ERC grant 321630 to G.W. The authors apologize for the omission of some studies owing to space constraints.

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  1. Catarina Felisberto-Rodrigues, Amit Meir, Marie S. Prevost, Adam Redzej and Martina Trokter: These authors contributed equally to this work.

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  1. Institute of Structural and Molecular Biology, University College London and Birkbeck, Malet Street, London, WC1E 7HX, UK

    Tiago R. D. Costa, Catarina Felisberto-Rodrigues, Amit Meir, Marie S. Prevost, Adam Redzej, Martina Trokter & Gabriel Waksman

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Glossary

Pili

Long appendages that are found on the surface of Gram-negative bacteria and are involved in bacterial attachment, motility and inter-bacterial communication.

Curli

Extracellular amyloid-like protein fibres produced by some bacteria, which are involved in adhesion, biofilm formation and surface colonization.

SecYEG translocon

Evolutionarily conserved machinery that transports cytosolic proteins through the cytoplasmic membrane of bacteria and archaea and through the membrane of the endoplasmic reticulum in eukaryotic cells.

Tat system

(Twin-arginine-translocation system). A system that transports fully folded protein substrates across the cytoplasmic membrane of bacteria and archaea, and the thylakoid membrane of plant chloroplasts.

ATP-binding cassette transporter

(ABC transporter). A member of a ubiquitous superfamily of membrane-bound pumps present in all prokaryotes, fungi, plants, yeast and animals. Directional substrate transport across a membrane bilayer is achieved by an ATP-dependent flipping mechanism from an inward- to an outward-facing conformation.

Pseudopilus

A short pilus-like periplasmic structure in the type II secretion system (composed of the GspG, GspH, GspI, GspJ and GspK pseudopilins) that is involved in substrate extrusion through the outer membrane channel.

Type IV pilus

(T4P). A surface appendage used by many pathogenic bacteria for surface motility, biofilm formation and adhesion at the initial stages of infection. T4Ps enable directional crawling (twitching motility) by cycles of repeated extension-adhesion and retraction-release movements driven by ATPases.

Pilotins

Outer membrane lipoproteins that are involved in secretin oligomerization, insertion and correct localization in the bacterial outer membrane.

Bitopic

A transmembrane protein that contains only one transmembrane segment.

Polytopic

A transmembrane protein that crosses the lipid bilayer twice or more.

Solid-state nuclear magnetic resonance spectroscopy

(Solid-state NMR spectroscopy). A powerful atomic-scale characterization technique applicable to systems that cannot be investigated by either solution NMR or X-ray crystallography, ranging from non-crystalline or poorly crystalline assemblies to protein aggregates or fibrils.

Rosetta modelling

A unified software package for computational protein modelling and functional design.

Conjugative plasmids

Self-transmissible plasmids that possess all of the necessary genes for their own mobilization by conjugation.

ClpV recognition motif

A motif present in the amino-terminal domain of TssC that recruits the ATPase ClpV.

Translocation and assembly module

(TAM). A nanomachine composed of two proteins (the outer membrane protein TamA and the inner membrane TamB subunit), which promotes efficient secretion of autotransporters in Proteobacteria.

Donor strand exchange

(DSE). Chaperone-assisted mechanism of type I pilus assembly in which the stabilizing β-strand that is donated by the chaperone is replaced by the amino-terminal extension of the subunit that is next in assembly.

Amyloids

A class of thread-like protein aggregates that self-assemble into insoluble toxic nanofibres. In bacteria, the accumulation of such fibres promotes the formation of a protective biofilm, whereas in humans they are involved in neurodegenerative diseases.

Entropy gradient

An energy gradient produced between two compartments when, in one compartment, the conformational entropy of a peptide or protein is reduced (usually by confinement) while in the other compartment it is not.

Chaperonins

A family of ATP-driven molecular chaperones that form large multisubunit machines to promote protein folding.

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Costa, T., Felisberto-Rodrigues, C., Meir, A. et al. Secretion systems in Gram-negative bacteria: structural and mechanistic insights. Nat Rev Microbiol 13, 343–359 (2015). https://doi.org/10.1038/nrmicro3456

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