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T3SS FliH protein family, which was found to bind and regulate the activity of
the ATPase (
Minamino and Macnab, 2000b
;
Blaylock et al., 2006
), and has sig-
nificant sequence similarity to the peripheral stalk of the F/V/A-ATPases (
Pallen
et al., 2006
), which acts as a stator to prevent rotation of the catalytic subunits.
Secondly, structural similarity has also been observed for the small flagellar T3SS
coiled-coil protein FliJ and the central stalk of the F/V/A-ATPases (
Ibuki et al.,
2011
), which transduces the rotational force between the membrane-embedded
and catalytic components. Both FliH and FliJ form complexes with the flagel-
lar T3SS ATPase and have orthologs in the T3SS injectisome (EscL family and
EscA family, respectively). The detected evolutionary relationship between the
soluble export apparatus components of the T3SS and the F/V/A-ATPases, and the
involvement of the PMF in T3SS transmembrane translocation, a pivotal feature
of F/V/A-ATPases, supports a possible common evolutionary origin and related
mechanism of these two transmembrane molecular machines.
MECHANISM OF SECRETION AND ASSEMBLY
Chaperones and effector recognition
The T3SS export apparatus must recognize and select a small number of effec-
tor proteins to export from the cellular milieu and these must be secreted in a
temporally regulated manner. Effector recognition and secretion is regulated by
a combination of a protein primary structure secretion signal, and by the binding
of effector proteins to cytoplasmic chaperones.
The T3SS secretion signal is commonly harbored in the N-terminal 20-30
residues of the effector proteins (
Sory et al., 1995
;
Schesser et al., 1996
). It is
remarkably variable in sequence, although it often shares similar physiochemi-
cal properties or sequence motifs (
Lloyd et al., 2002
;
Arnold et al., 2009
). One
common feature of the signal sequence that has recently become evident is its
intrinsically disordered nature and lack of tertiary structure (
Lilic et al., 2006
).
Intrinsically disordered proteins have been implicated in protein-protein inter-
actions where they can undergo disorder-order transition upon binding. Indeed,
such a transition has been demonstrated for the interaction of the
Yersinia
effec-
tor YopE and its cognate chaperone SycE (
Rodgers et al., 2008
). In addition,
secretion signals have also been documented in internal sequences and also at
the C-terminus of effectors. For example, the EPEC translocon protein EspB has
been shown to have internal and C-terminal motifs that determine secretion (
Chiu
et al., 2003
) and the EPEC effector protein Tir (for translocated intimin receptor)
has been shown to have a C-terminal signal sequence (
Allen-Vercoe et al., 2005
).
T3SS chaperones are usually small acidic, often dimeric, cytoplasmic proteins
that bind to many effector proteins destined for secretion through the injectisome
and exert their function in an ATP-independent manner. In addition to the secretion
signal, some T3SS substrates require a cognate chaperone in order to be secreted.
Chaperone proteins have been classified according to their binding partners: class
IA chaperones bind one (or related) substrate protein while IB chaperones are more
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