Biology Reference
In-Depth Information
of both factors is dependent on phosphorylation (
Dardente, Fortier,
Martineau, & Cermakian, 2007
).
The DNA-binding region comprises about 100 residues at the
N-terminal and is organized in a basic helix-loop-helix motif (bHLH).
Two haem-binding PAS domains are present (PAS-A and PAS-B) of
about 130 residues each (
Dioum et al., 2002
). At the C-terminal, there
are about 400 additional residues that form a yet-uncharacterized domain
(
Gu, Hogenesch, & Bradfield, 2000
).
The RR spectra of the PAS-B domain in the Fe(III) and Fe(II) form are a
mixture of high-spin penta-coordinated and low-spin hexa-coordinated
forms. Mutational studies reveal that His335 is the proximal axial ligand
(
Koudo et al., 2005
). In the PAS-B Fe(II)-CO form, there is also a hydrogen
bond present between the CO molecule and a distal histidine residue that
stabilizes the exogenous ligand in place (
Koudo et al., 2005
). On the other
hand, the dominant species of the PAS-A domain is hexa-coordinated with
an equilibrium between the Cys-Fe-His and His-Fe-His forms. In the
bHLH-PAS-A construct, this equilibrium is shifted towards the bis-histidine
coordination (
Uchida, Sagami, Shimizu, Ishimori, & Kitagawa, 2012
). The
mutation of one of these two histidine axial ligands dramatically decreases
the transcriptional capability of NPAS2 (
Ishida, Ueha, & Sagami, 2008
).
The
for bHLH-PAS-A (
k
onCO
¼
ligand-binding kinetics
3.3
10
7
mol
1
s
1
), PAS-A (
k
onCO
<
10
5
mol
1
s
1
), and PAS-B (
k
onCO
¼
7.7
10
5
mol
1
s
1
) have been measured. These differences in the
CO-binding affinities highlight the role of the bHLH domain in the stabi-
lization of the haem-binding in NPAS2 (
Koudo et al., 2005; Mukaiyama
et al., 2006
).
The target genes of NPAS2 are numerous. Lack or non-functional muta-
tions in NPAS2 are related to several aberrant states. The best-characterized
alterations involve the circadian rhythm (
Dudley et al., 2003; Evans et al.,
2013; Johansson et al., 2003; Wisor et al., 2008
), but during the past years,
more and more disorders and diseases have been linked to dysfunctions of
NPAS2: for example, problems in the acquisition of specific types of mem-
ory (
Garcia et al., 2000
), autistic disorder (
Nicholas et al., 2007
), blood pres-
sure (
Curtis et al., 2007
), Parkinson's disease (
Anantharam et al., 2007
),
winter depression (
Partonen et al., 2007
) and depression (
Lavebratt,
Sjoholm, Partonen, Schalling, & Forsell, 2010
), thrombogenesis
(
Westgate et al., 2008
), prostate cancer (
Zhu et al., 2009
), fertility
(
Kovanen, Saarikoski, Aromaa, Lonnqvist, & Partonen, 2010
), and chronic
fatigue syndrome (
Smith, Fang, Whistler, Unger, & Rajeevan, 2011
). The
