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EcoSal Plus

Domain 8:


Pili Assembled by the Chaperone/Usher Pathway in and

MyBook is a cheap paperback edition of the original book and will be sold at uniform, low price.
  • Authors: Glenn T. Werneburg1, and David G. Thanassi3
  • Editor: Michael S. Donnenberg5
    Affiliations: 1: Department of Molecular Genetics and Microbiology; 2: Center for Infectious Diseases, Stony Brook University, Stony Brook, NY 11794; 3: Department of Molecular Genetics and Microbiology; 4: Center for Infectious Diseases, Stony Brook University, Stony Brook, NY 11794; 5: Virginia Commonwealth University School of Medicine, Richmond, VA
  • Received 06 September 2017 Accepted 16 January 2018 Published 13 March 2018
  • Address correspondence to David G. Thanassi, [email protected]
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  • Abstract:

    Gram-negative bacteria assemble a variety of surface structures, including the hair-like organelles known as pili or fimbriae. Pili typically function in adhesion and mediate interactions with various surfaces, with other bacteria, and with other types of cells such as host cells. The chaperone/usher (CU) pathway assembles a widespread class of adhesive and virulence-associated pili. Pilus biogenesis by the CU pathway requires a dedicated periplasmic chaperone and integral outer membrane protein termed the usher, which forms a multifunctional assembly and secretion platform. This review addresses the molecular and biochemical aspects of the CU pathway in detail, focusing on the type 1 and P pili expressed by uropathogenic as model systems. We provide an overview of representative CU pili expressed by and , and conclude with a discussion of potential approaches to develop antivirulence therapeutics that interfere with pilus assembly or function.

  • Citation: Werneburg G, Thanassi D. 2018. Pili Assembled by the Chaperone/Usher Pathway in and , EcoSal Plus 2018; doi:10.1128/ecosalplus.ESP-0007-2017


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Gram-negative bacteria assemble a variety of surface structures, including the hair-like organelles known as pili or fimbriae. Pili typically function in adhesion and mediate interactions with various surfaces, with other bacteria, and with other types of cells such as host cells. The chaperone/usher (CU) pathway assembles a widespread class of adhesive and virulence-associated pili. Pilus biogenesis by the CU pathway requires a dedicated periplasmic chaperone and integral outer membrane protein termed the usher, which forms a multifunctional assembly and secretion platform. This review addresses the molecular and biochemical aspects of the CU pathway in detail, focusing on the type 1 and P pili expressed by uropathogenic as model systems. We provide an overview of representative CU pili expressed by and , and conclude with a discussion of potential approaches to develop antivirulence therapeutics that interfere with pilus assembly or function.

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Image of Figure 1
Figure 1

Pilus subunits translocate from the cytoplasm to the periplasm as unfolded polypeptides via the Sec system. Subunit folding occurs upon interaction with the pilus chaperone (yellow) in the periplasm. Chaperone-subunit complexes then interact with the OM usher for exchange of chaperone-subunit for subunit-subunit interactions, ordered assembly of the pilus fiber, and secretion through the usher channel to the cell surface. The usher is depicted with its β-barrel channel domain in the OM and its plug, N, C1, and C2 domains labeled. The N domain forms the initial binding site for chaperone-subunit complexes, and the C domains provide a second binding site for the assembling pilus fiber. Chaperone-adhesin complexes have the highest affinity for the usher and initiate pilus assembly by binding to the usher N domain, with subsequent handoff to the usher C domains. Repeated rounds of chaperone-subunit targeting to the usher N domain and subunit-subunit interaction then lead to assembly and secretion of the pilus fiber in a top-down manner. Models of fully assembled type 1 (Fim), P (Pap), and Afa pilus fibers are shown.

Citation: Werneburg G, Thanassi D. 2018. Pili Assembled by the Chaperone/Usher Pathway in and , EcoSal Plus 2018; doi:10.1128/ecosalplus.ESP-0007-2017
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Figure 2

(A) Gene clusters, including upstream regulatory regions, are shown for P (), type 1 (), and Dr/Afa pili, with the functions of the genes indicated. (B) Regulatory region of the gene cluster, shown in phase-OFF and phase-ON states. Lrp binding to the GATC site turns off expression from the promoter. Binding of Lrp, together with PapI, to the GATC site allows Dam methylation of GATC, resulting in phase-ON expression. Production of PapB during phase-ON expression initiates a positive feedback loop through upregulation of PapI. (C) Regulatory region of the gene cluster, showing the phase-OFF and phase-ON orientations of the switch region. The left and right inverted repeat sequences ( and ) that flank the S switch are indicated. Binding of H-NS maintains in the phase-OFF position, whereas binding of IHF and Lrp favors phase-ON expression.

Citation: Werneburg G, Thanassi D. 2018. Pili Assembled by the Chaperone/Usher Pathway in and , EcoSal Plus 2018; doi:10.1128/ecosalplus.ESP-0007-2017
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Figure 3

(A) Structure of a FimC-H chaperone-adhesin complex (PDB ID: 1QUN) from the type 1 pilus system. The FimC chaperone is in yellow and the FimH adhesin in green, with the FimH lectin and pilin domains indicated. The chaperone is engaged in donor strand complementation (DSC) with the subunit. The chaperone donates its G1 β-strand (in blue) to complete the Ig fold of the FimH pilin domain. (B) Structure of a FimG-FimH subunit-subunit complex (PDB ID: 4J3O) from the type 1 pilus system. FimH is depicted as in (A) and FimG is in orange. The N-terminal extension (Nte) of FimG is engaged in donor strand exchange (DSE) with FimH. The Nte of FimG completes the Ig fold of the FimH pilin domain. (C) Topology diagrams depicting the Ig folds of the FimG (orange) and FimF (red) pilin domains. FimF is depicted in DSC with the donated G1-strand of the FimC chaperone, which is inserted parallel to the FimF F-strand. FimG is depicted in DSE with the Nte of FimF, which is inserted antiparallel to the FimG F-strand. (D) and (E) Structures of the lectin domains of the FimH (type 1 pili; PDB ID: 1KLF) and PapG (P pili; PDB ID: 1J8R) adhesins, with bound mannose and globoside molecules, respectively. The sugars are depicted in dark gray stick representation.

Citation: Werneburg G, Thanassi D. 2018. Pili Assembled by the Chaperone/Usher Pathway in and , EcoSal Plus 2018; doi:10.1128/ecosalplus.ESP-0007-2017
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Figure 4

(A) and (C) Structure of FimD (PDB ID: 3OHN), shown from side (A) and top (C) views. The transmembrane β-barrel channel domain is pictured in light blue and the plug domain in pink. The plug domain is positioned laterally within the β-barrel domain, closing the usher channel. The N, C1, and C2 domains are not present in this structure. (B and D) Structure of activated FimD (PDB ID: 3RFZ), shown from side (B) and top (D) views. The channel and plug domains are depicted as in (A), the N domain is in dark blue, the C1 domain is in cyan, and the C2 domain is in purple. In the activated usher, the plug is expelled from the channel and resides adjacent to the N domain in the periplasm.

Citation: Werneburg G, Thanassi D. 2018. Pili Assembled by the Chaperone/Usher Pathway in and , EcoSal Plus 2018; doi:10.1128/ecosalplus.ESP-0007-2017
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Figure 5

(A) Cartoon depictions of domain organization and color coding for the Fim proteins shown in panels (B through F). (B) Structure of FimD (PDB ID: 3OHN) with the transmembrane β-barrel channel closed by the plug domain. (C) Structure of the FimD N domain bound to a FimC-FimH pilin domain complex (PDB ID: 1ZE3). (D) Structure of the activated FimD usher with bound FimC-H chaperone-adhesin complex (PDB ID: 3RFZ). The FimH lectin domain is inserted inside the usher channel and the FimH pilin domain and bound FimC chaperone are located at the usher C domains. The FimD plug domain resides adjacent to the N domain in the periplasm. Structure of the FimD-C-F-G-H type 1 pilus assembly intermediate (PDB ID: 4J3O). The FimF-G-H pilus tip fiber is traversing the usher channel, with FimH exposed to the cell surface, and FimF bound by FimC located at the usher C domains. (F) Model for type 1 pilus assembly at the FimD usher. In its resting () state, the FimD plug domain resides laterally within the usher channel (structure shown in B). The plug closes the usher channel and also functions to mask the C domains. Pilus assembly initiates with the binding of a FimC-H chaperone-adhesin complexes to the FimD N domain (step 1; structure shown in C). FimC-H binding to the N domain activates the usher by triggering opening of the plug domain and unmasking of the C domains. FimC-H then undergoes handoff from the N to the C domains, concomitant with insertion of the FimH lectin domain into the usher channel (step 2; structure shown in D). The usher N domain functions to recruit the next chaperone-subunit complex, FimC-G, from the periplasm (step 3). The FimC-G complex bound at usher N domain is perfectly positioned to undergo DSE with FimC-H bound at the C domains, forming the first link in the pilus fiber and displacing FimC from FimH. FimC-G is then handed off from the N to the C domains, concomitant with movement of the nascent pilus fiber through the usher channel toward the cell surface (step 4). Repeated cycles of chaperone-subunit recruitment and DSE (step 5) then result in assembly and secretion of the pilus tip (structure shown in E) and finally the pilus rod.

Citation: Werneburg G, Thanassi D. 2018. Pili Assembled by the Chaperone/Usher Pathway in and , EcoSal Plus 2018; doi:10.1128/ecosalplus.ESP-0007-2017
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Table 1

CU pili present in and

Citation: Werneburg G, Thanassi D. 2018. Pili Assembled by the Chaperone/Usher Pathway in and , EcoSal Plus 2018; doi:10.1128/ecosalplus.ESP-0007-2017

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