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mediate this transfer. With the chaperone-adhesin complex bound primarily
to CTD1, the lectin domain of the adhesin lies in the channel lumen, and
the NTD-plug complex is available for the incoming chaperone-tip subunit
complex.
4.
Next, the NTD-plug complex recruits the upcoming chaperone-tip subunit
complex, while the chaperone-adhesin complex is bound to the CTDs.
A unique conformation in the NTD-plug complex brings the tip subunit
into the ideal orientation with respect to the adhesin for DSE, allowing for
the assembly of the growing pilus fiber. The reaction results in the displace-
ment of the chaperone off of the CTD, allowing the newly incorporated
chaperone-subunit complex to dock on the CTDs. The process repeats for
all chaperone-subunit complexes in order of the subunit ordering observed
in the mature pilus fiber.
5.
Ultimately, the chaperone-terminator complex docks on the NTD-plug
complex. Unable to bind CTD2 and unable to undergo DSE due to its lack
of a P5 pocket, the chaperone-terminator complex signals the end of pilus
growth. The plug may bind the chaperone-terminator complex with its βC,
βB, βE, and βF side and swing into the β-barrel lumen with that same side
facing the extracellular space, as seen in the apo state. The mature pilus fiber
anchors to the outer membrane in this fashion and is ready to perform its
adhesive function.
Overall, this model provides insight into how the usher assembles the CU pilus.
With domain affinities, molecular snapshots of pilus biogenesis steps, and
genetic and biochemical evidence, we can now understand how the usher effi-
ciently transfers chaperone-subunit complexes using its periplasmic domains
to perform its catalysis of fiber growth. Further work will be required to gain a
deeper mechanistic understanding of this molecular machine to provide knowl-
edge of targetable protein interfaces and dynamic processes for next generation
small-molecule pilicides that can inhibit these virulent adhesive pili.
ROLE OF CU PILI IN INFECTIONS
UPEC introduced to the urinary tract from the fecal flora is the leading caus-
ative agent of urinary tract infections (UTIs), responsible for 85% of commu-
nity-acquired UTIs (see Chapter 9) (
Ronald et al., 2001
). Genetic, biochemical,
and imaging studies accompanied by murine models of UTIs revealed that CU
pili are crucial factors for causing this disease.
For instance, type 1 pili, encoded by the
fim
operon, are required for blad-
der infection in a murine model of UTI (
Hultgren et al., 1985
;
Connell et al.,
1996
;
Mulvey et al., 1998
;
Anderson et al., 2003
;
Wright et al., 2007
) and for
biofilm formation in rat kidneys (
Melican et al., 2011
). The adhesin of type 1
pili, FimH, mediates binding to the mannosylated receptors on the surface of
bladder urothelial cells for colonization and invasion of the superficial umbrella
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