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ensure the activation of Rr CooA only when CO intracellular concentration
occurs at a high ( m M) level for sufficiently long time (longer than 1 min), and
the activation is efficient over a narrow range of CO concentrations ( Puranik
et al., 2004 ).
As expected, the CO-binding kinetics is influenced by the presence of
the DNA-binding domain and, even more, when DNA is bound. It has
been proposed that the second domain helps to form a hydrophobic trap
for CO, whereas the DNA binding rigidifies the whole structure, thus opti-
mizing the CO-dependent signal ( Benabbas, Karunakaran, Youn, Poulos, &
Champion, 2012 ).
A Rr CooA homologue (29% identity) has been identified in the thermo-
philic CO-oxidizing bacterium named Carboxydothermus hydrogenoformans
( Ch CooA) ( Inagaki et al., 2005 ), which is activated, next to CO, also upon
NO binding ( Clark et al., 2006 ). This unexpected activation is explained by
the formation of a six-coordinated Fe(II)-NO adduct, where in Rr CooA,
NO forms a five-coordinated form ( Clark et al., 2006; Reynolds
et al., 2000 ).
The crystal structure of Ch CooA bound to exogenous imidazole is
known and provides further atomic-resolution information on the molec-
ular mechanisms that drive ligand-binding-dependent activation ( Komori,
Inagaki, Yoshioka, Aono, & Higuchi, 2007 ). Upon CO binding, the
N-terminal region is displaced and bends, creating a bridge between the
two major domains. This rearrangement determines structural modifications
in the D-helix, which cause the movement of the DNA-binding domains
( Fig. 1.3 B). The DNA-binding domains slide closer to the effector-binding
domains, thus exposing the F-helix for unambiguous DNA-recognition
( Borjigin et al., 2007 ).
2.2.1.2 The neuronal PAS domain protein 2
The NPAS2 is a dimeric mammalian transcription factor mainly expressed in
the forebrain under the control of the retinoic acid-related orphan receptor y
( Hogenesch et al., 1998; Takeda, Kang, Angers, & Jetten, 2011; Zhou et al.,
1997 ). It is known that the NPAS2 transcription function is strongly
inhibited upon CO binding ( Uchida et al., 2005 ).
Evidence shows that NPAS2 interacts with the brain and muscle Arnt-
like protein 1 transcription factor (BMAL1) and, as such, functions as a
hetero-dimer ( Reick et al., 2001 ). NPAS2:BMAL1, in particular, is
involved in the expression of genes of the circadian rhythm ( Dudley
et al., 2003; Rutter, Reick, Wu, & McKnight, 2001 ), and the activation
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