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Structural biology of the chaperone–usher pathway of pilus biogenesis

Nature Reviews Microbiology volume 7, pages 765–774 (2009)Cite this article

Key Points

  • Chaperone–usher (CU) pili are assembled at the outer membrane by two proteins, a periplasmic chaperone, which provides the scaffold for the correct folding of pilins, and an outer-membrane protein called the usher, which forms a dimeric complex at the outer membrane to recruit and polymerize chaperone–subunit complexes and translocate the growing pilus to the outer surface. CU pili comprise linear, unbranched polymers of several hundreds to thousands of 12–20 kDa pilin subunits. This Review focuses on the rod-like fimbrial organelles, particularly uropathogenic Escherichia coli P and type 1 pili (the Pap and Fim systems, respectively).

  • Over the past decade, a plethora of structural information has been gathered about the various players that participate in P and type 1 pilus biogenesis, and these structural data, including the newly determined usher structures, are reviewed in detail.

  • Pilin subunits contain an incomplete, immunoglobulin-like fold that lacks the carboxy-terminal β-strand, which results in the presence of a large hydrophobic groove. When the chaperone–pilin complex is formed, a structural motif on the G1 strand of the chaperone is inserted into this groove. This donor strand complementation reaction is discussed in light of the most recent structural and biochemical data.

  • Pilin subunits also contain an amino-terminal extension (Nte) peptide that is disordered in the chaperone–subunit complex. During polymerization, the Nte on the incoming pilin subunit replaces the chaperone G1 strand, and this donor strand exchange reaction, including the 'zip-in, zip-out' mechanism, is also reviewed.

  • Recent structural data have indicated that only a single usher pore in the dimeric usher complex is used for pilus secretion. This model is discussed in detail.

  • Bacterial attachment to mucosal surfaces can be the result of the specific recognition of a pilus-associated adhesin by a host cell receptor. The molecular basis of receptor recognition of the FimH and PapG adhesins is described.

  • Finally, the complex role of CU pili in the pathogenesis of urinary tract infections is summarized, along with the prospects for using CU pili as a target for novel antibacterial therapies.

Abstract

The chaperone–usher (CU) pathway of pilus biogenesis is the most widespread of the five pathways that assemble adhesive pili at the surface of Gram-negative bacteria. Recent progress in the study of the structural biology of the CU pathway has unravelled the molecular basis of chaperone function and elucidated the mechanisms of fibre assembly at the outer membrane, leading to a comprehensive description of each step in the biogenesis pathway. Other studies have provided the molecular basis of host recognition by CU pili. The knowledge that has been gathered about both the assembly of and host recognition by CU pili has been harnessed to design promising antibiotic compounds.

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Figure 1: P and type I pili.
Figure 2: Donor strand complementation and donor strand exchange.
Figure 3: The concerted 'zip-in, zip-out' mechanism for donor strand exchange.
Figure 4: The structural biology of the usher.
Figure 5: Receptor binding and pilus biogenesis inhibition.

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Acknowledgements

This work was funded by Medical Research Council grant 85602 to G.W. and US National Institutes of Health grant 49950 to S.J.H.

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  1. Center for Women's Infectious Disease Research, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8230, St Louis, Missouri 63110, USA. hultgren@borcim.wustl.edu

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

    Gabriel Waksman & Scott J. Hultgren

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Glossary

Chaperone–usher pilus

A bacterial cell surface appendage that is assembled by the chaperone–usher pathway of pilus biogenesis.

Curli

A type of fimbria that mediates binding to components of the extracellular matrix and is often implicated in biofilm formation.

Type IV pilus

An elongated, flexible appendage that extends from the surface of Gram-negative bacterial cells and is used for adhesion and for cell motility (twitching motility).

Type III secretion needle

A needle-like secretion apparatus in Gram-negative bacteria that forms pores in host membranes and allows the injection of virulence factors from the bacterial cytoplasm into the cytosol of host cells.

Type IV secretion pilus

A pilus that is formed as part of the versatile secretion systems that are found in Gram-negative and Gram-positive bacteria. It can secrete a wide range of substrates, including protein–protein and protein–DNA complexes, and can directly target eukaryotic cells.

Molecular dynamics

A form of computer simulation that calculates the time- dependent behaviour of atoms and molecules, providing information about the motion of the atoms and the resultant conformational changes in the molecules over time or during an interaction.

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Waksman, G., Hultgren, S. Structural biology of the chaperone–usher pathway of pilus biogenesis. Nat Rev Microbiol 7, 765–774 (2009). https://doi.org/10.1038/nrmicro2220

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