Oct and Sox
POU/HMG/DNA
complex
Ariel Bartholomew '13 and Kate Haller '13
Contents:
I. Introduction
The Oct and Sox transcription factors are present
during early mammalian embryonic cell development and control
specifically different aspects of neural development. Oct4 and Sox2
are two of the focused transcription factors whose combinations helped
to established the first three lineages in the mammalian embryo. The
interaction of these two play a key role in determining the many
possible cell types in early embryogenesis. Low number of
transcription factors are responsible for the development of the
entire organism, forming multiprotein complexes on DNA. Thus
establishing functional partnerships and transcriptional outcomes.
Very few transcription factors are responsible for developing entire
organisms. Through the formation of multi-protein complexes on the
DNA, different functional partnerships and transcriptional outcomes
are established. The Oct and Sox transcription factors are present
during early mammalian embryonic cell development and control
specifically different aspects of neural development. Oct and Sox
transcription factors are a part of the larger ternary POU/HMG/DNA
complex. Oct proteins are transcription factors of the POU domain,
while Sox proteins are transcription factors of the HMG
domain.
II. HMG
Sox2 induces a bend in the DNA of the ternary
complex and binds in the minor groove of the DNA, forming a
HMG/DNA interaction surface similar to the size of the POU/DNA
interaction at about 1350 Å HMG
bends the DNA 90
degrees towards the major groove. Hydrophopic
side chains are inserted into the DNA, causing a bend
of the DNA toward the major helix
. Sox2 is sequence
specific when binding to DNA,this
binding is mediated by hydrogen bonds
. The C-terminus
of the HMG domain
(residues 68-79)
interacts
with DNA and forms a protein-protein interface
between helices 1 and 2 on Oct1
.
Serine rich
domain and the C-terminal
end are necessary to enhance gene expression (amino acids
206-319)
. Sox2 N-terminus
region contains the DNA
binding domain Sox2
1-180. Sox2 has lower affinity when binding DNA
on its own rather than in a ternary complex
. Sox2-HMG domain
interacts with the compressed minor groove, suggesting its a
factor in the complex formation Sox2-HMG
domain will adopt an L-shape structure
. The compressed minor groove is positioned by Tyr
72 and Pro 74
.
III.
POU
The POU The POU
binding domain is a highly charged region comprised of ~160 amino
acids. The whole region is referred to as the POU domain, for the
Pit-1, Oct-1 and Oct-2, and unc-86 region of sequence similarity.
This domain’s sequence is similar to three mammalian transcription
factors, Pit-1, Oct-1, and Oct-2. The POU domain consists of two
subdomains, a C-terminal POU
homeodomain (POUhd) and an N-terminal POU-specific
(POUs) domain
. These two domains are connected by a flexible
linker and interact with DNA in a two-way manner
. The individual POU domains can bind DNA, but only very weakly.
However, they have strong sequence-specific affinity when linked.
Oct-1 and Oct-2
recognize the same octameric sequence, ATGCAAAT. The POU
domain is appropriate for sequence-specific binding. Both subdomain
of POU contains a helix-turn-helix
region important for DNA binding
. The domain may also be involved in protein-protein interactions.
POUs forms protein-protein
interactions as well as protein-DNA
interactions in
order to stabilize the POUs-DNA complex. Lys17 Thr26
Arg 20 are the 3 main residues
involved in these interactions. The POUs
domain is responsible for binding affinity as well as binding
specificity through direct DNA
contacts. Ser 48
and Arg 20 on POUs H-bond with a phosphate group on the DNA
.
IV.
General
Structure
The Oct and Sox transcription
factors interact with each other through their DNA binding domains
in order to regulate transcription synergistically. Sox
and POUs interact
mostly through a hydrophobic boundary, surrounded by a ring of
electrostatic interactions
.However,
a
salt brigde between R75
on HMG
and D29
of POU
is the only sequence specific interaction
between the POUs and HMG domains
. This single sequence interaction could be the reason for the random
formation of the POU/HMG/DNA complex.
Combinatorial control is a mechanism
that integrates different signaling pathways in an ideal manner to
provide a more complex regulatory network based on a finite number
of transcription factors. This
mechanism is accomplished through
transcription factors with adaptable DNA and protein binding
surfaces, which allows different combinations of these proteins to
interact on specific promoter elements to drive synergistic
transcription regulation. Both Oct3/4 and Oct1 can bind adjacently
to Sox2 on the FGF4
and UTF1 promoter elements
.FGF4 is able to made three additional base pairs between the Oct and
Sox binding sites compared to UTF1.On
FGF4,
only 4
residues on POUs
and 2
residues on Sox2
are involved in the protein-protein interface
. The amount of cooperatively exerted by each protein is dependent of
the amount of Oct4 and Sox2 present in the
cell.
Oct and Sox transcription factors
regulate based on the standards of combinatorial control. The
binding region of the Sox proteins, HMG, is a defined
DNA binding region
known as the
HMG-box binding domain
. This binding domain recognizes
variations of the sequence CTTTGTT. Oct
proteins bind though the POU domains, POUs and POUhd, and recognize
the octamer sequence ATGCTAAT.
Oct4
and
Sox2 dimerize onto
DNA in distinct conformational
arrangements. Oct factors of the POU
domain can homodimerize two distinct enhancers
by separating the dimeriazion surface patches
.
interaction surfaces. One that interacts
between the 3rd
α-helix and POUs and one interaction
on the
C-terminus
end interacting with the loop
region on POUs between the 1st and
2nd helixes. Depending on which enhancer is
present, will determine where POUs
interacts on the Sox2
domain
. The distance between the DNA motifs and the binding sites on each
domain is essential to selecting which
interface of Sox2 is selected. POU and SOX
proteins interact selectively with other
conserved domains POU and HMG all binding to
DNA. DNA enhancer region of the target genes
is responsible for the proper spacial
arrangement of the glue-like interaction
domains on their surface.
VI.
References
Grenfell,
S.J.,
Latchman D.S., and Thomas N.S.B. 1996. CT-1 and Oct-2 DNA-binding
site specificity is regulated
in vitro by different kinases. Biochem. J. 315: 889-893.
Herr
W., Sturm, R.A., Clerc, R.G., Corcoran, L.M., Baltimore, D.,
Sharp, P.A., Ingraham, H.A., Rosenfeld,M.G.,
Finney, M., Ruvkun, G., and Horvitz, R.H. 2011. The POU domain: a
large conserved region in the mammalian pit-1,
oct-1, oct-2, and Caenorhabditis elegans unc-86
gene products. Genes & Development 2:1513-1516.
Nowling,
T. K., L. R.
Johnson, M. S.
Wiebe, and A.
Rizzino. 2000.
Identification
of the
transactivation
domain of the
transcription
factor Sox-2
and an
associated
co-activator.
J. Biol. Chem.
275:3810-3818.
Remenyi,
A., Lins, K.,
Nissen, L.J.,
Reinbold, R.,
Scholer, H.R.,
et al. Crystal
structure of a
POU/HMG/DNA
ternary
complex
suggests
differential
assembly of
Oct4 and Sox2
on two
enhancers.
Genes Dev.
2003;17:2048–2059.
Remenyi,
A., Scholer,
H.R., and
Wilmanns M.
2004.
Combinatorial
Control of
Gene
Expression.
Nature
Structural
&
Molecular
Biology.11:
812-815.
Sturm,
R.A.,
and W. Herr. 1988. The POU domain is
a bipartite DNA-binding structure. Nature 336:
601-604.
Williams,
D.C., Cai,
D.C., M., and
G.M. Clore.
Molecular
basis for
synergistic
transcriptional
activation by
Oct1 and Sox2
revealed from
the solution
structure of
the 42-kDa
Oct1 center
dot Sox2
center dot
Hoxb1-DNA
ternary
transcription
factor
complex. J.
Biol. Chem.
2004;279:1449-1457.
Back
to Top