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molecules, protein-protein interactions, and other processes (
Heikaus,
Pandit, & Klevit, 2009
). They are distantly related to PAS domains, another
superfamily with the same basic fold (
Anantharaman, Koonin, & Aravind,
2001
), both of which are involved in many signal transduction pathways
and protein regulatory and sensory systems (
Anantharaman et al., 2001;
Aravind & Ponting, 1997
). Several gas sensor proteins are identified
adopting a GAF domain that binds a haem, Fe-S cluster (
Nakajima et al.,
2010
) or non-haem iron (
Bush, Ghosh, Tucker, Zhang, & Dixon, 2011;
D'Autr´aux, Tucker, Dixon, & Spiro, 2005
) as the active site for gas sensing.
DosS and DosT from
M.
tuberculosis
are most extensively studied
among them.
The sensor kinases DosS (also known as DevS) and DosT activate the
transcriptional regulator DosR (also known as DevR) in response to both
hypoxia and non-lethal level of NO. The DosS/DosR and DosT/DosR
two-component signal transduction systems regulate the expression of the
dosR
regulon that is responsible for early adaptation to these stimuli as well
as for initiating entrance of
M. tuberculosis
into non-replicating persistent
state. DosS and DosT each contain two tandem GAF domains and a histi-
dine kinase domain in their N-terminal and C-terminal regions, respec-
tively. Both in DosS and DosT, the first GAF domain (GAF-A) contains
a haem, while the second GAF domain (GAF-B) does not (
Sardiwal
et al., 2005; Sousa, Tuckerman, Gonzalez, & Gilles-Gonzalez, 2007
).
The second GAF domain (GAF-B) is suggested to help in the formation
of a better-defined distal haem pocket of the GAF-A domain through inter-
domain interactions within DosS (
Lee et al., 2008
). The activation of the
response regulator DosR occurs through autophosphorylation of either
DosS or DosT followed by transfer of the phosphate to DosR (
Honaker,
Dhiman, Narayanasamy, Crick, & Voskuil, 2010; Saini et al., 2004
).
The kinase activities of DosS and DosT are dependent of the coordina-
tion state of the haem. In the both cases of DosS and DosT, kinase activity is
observed when the haem is a 5-coordinate ferrous (Fe
2
þ
) form, CO- or
NO-bound forms (Fe
2
þ
-CO or Fe
2
þ
-NO) but is strongly inhibited in an
oxy (Fe
2
þ
-O
2
) form (
Sousa et al., 2007; Yukl, Ioanoviciu, Nakano, Ortiz
de Montellano, &Mo
¨
nne-Loccoz, 2008
). The activities of DosS and DosT
are inhibited by about 84% and 98%, respectively, upon O
2
binding to the
ferrous haem (
Sousa et al., 2007
). These results indicate that both of DosS
and DosT are direct O
2
sensor proteins.
Kim, Park, Ko, Kim, and Oh (2010)
have proposed that the presence of
both DosS and DosT paralogues in
M. tuberculosis
is not a functional
