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PDBsum entry 1nwq
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Transcription/DNA
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PDB id
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1nwq
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Contents |
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* Residue conservation analysis
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DOI no:
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J Biol Chem
278:15178-15184
(2003)
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PubMed id:
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Structural basis for DNA recognition by the basic region leucine zipper transcription factor CCAAT/enhancer-binding protein alpha.
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M.Miller,
J.D.Shuman,
T.Sebastian,
Z.Dauter,
P.F.Johnson.
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ABSTRACT
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CCAAT/enhancer-binding proteins (C/EBPs) are basic region leucine zipper (bZIP)
transcription factors that regulate cell differentiation, growth, survival, and
inflammation. To understand the molecular basis of DNA recognition by the C/EBP
family we determined the x-ray structure of a C/EBPalpha bZIP polypeptide bound
to its cognate DNA site (A(-5)T(-4)T(-3)G(-2)C(-1)G(1)C(2)A(3)A(4)T(5)) and
characterized several basic region mutants. Binding specificity is provided by
interactions of basic region residues Arg(289), Asn(292), Ala(295), Val(296),
Ser(299), and Arg(300) with DNA bases. A striking feature of the C/EBPalpha
protein-DNA interface that distinguishes it from known bZIP-DNA complexes is the
central role of Arg(289), which is hydrogen-bonded to base A(3), phosphate,
Asn(292) (invariant in bZIPs), and Asn(293). The conformation of Arg(289) is
also restricted by Tyr(285). In accordance with the structural model, mutation
of Arg(289) or a pair of its interacting partners (Tyr(285) and Asn(293))
abolished C/EBPalpha binding activity. Val(296) (Ala in most other bZIPs)
contributes to C/EBPalpha specificity by discriminating against purines at
position -3 and imposing steric restraints on the invariant Arg(300). Mutating
Val(296) to Ala strongly enhanced C/EBPalpha binding to cAMP response element
(CRE) sites while retaining affinity for C/EBP sites. Thus, Arg(289) is
essential for formation of the complementary protein-DNA interface, whereas
Val(296) functions primarily to restrict interactions with related sequences
such as CRE sites rather than specifying binding to C/EBP sites. Our studies
also help to explain the phenotypes of mice carrying targeted mutations in the
C/EBPalpha bZIP region.
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Selected figure(s)
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Figure 4.
Fig. 4. Architecture of the protein surface complementary
to the cognate DNA. A, critical interactions in the C/EBP  protein-DNA
interface. Protein side chains are represented as sticks and DNA
as balls-and-sticks. Selected electrostatic and van der Waals
interactions are depicted as dashed and dotted lines,
respectively. B, comparison of conformations of the conserved
side chains in the basic regions of C/EBP (green) and
GCN4 (gray). The side chain of the invariant Asn residue from
the PAP1 structure is shown in yellow.
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Figure 5.
Fig. 5. Details of the C/EBP protein-DNA
interface. A, hydrophobic cluster involving two thymine moieties
from the C/EBP site and side chains of Val296 and Arg300. B,
interactions defining possible conformation of Arg300. The side
chain of the homologous Arg residue from GCN4 (one observed
conformation) is shown in gray. C, comparison of the protein
environment of base 2 in C/EBP (green) and
GCN4 (gray) complexes. Hydrophobic interaction of the methyl
group from T2 and Ala occurring in GCN4 is marked by a dotted
line. Note that C^2 in the C/EBP site does not interact with
Val296, and its position is displaced relative to T2 from the
GCN4-CREB complex. D, electron density (2F[o]  F[c])
contoured at 1.0  (gray) and
1.8 (green;
DNA only) is shown for important residues, with the coordinates
superimposed.
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The above figures are
reprinted
by permission from the ASBMB:
J Biol Chem
(2003,
278,
15178-15184)
copyright 2003.
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Figures were
selected
by an automated process.
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Literature references that cite this PDB file's key reference
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PubMed id
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Reference
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I.Paz-Priel,
S.Houng,
J.Dooher,
and
A.D.Friedman
(2011).
C/EBPα and C/EBPα oncoproteins regulate nfkb1 and displace histone deacetylases from NF-κB p50 homodimers to induce NF-κB target genes.
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Blood,
117,
4085-4094.
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J.Jin,
G.L.Wang,
P.Iakova,
X.Shi,
S.Haefliger,
M.Finegold,
and
N.A.Timchenko
(2010).
Epigenetic changes play critical role in age-associated dysfunctions of the liver.
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Aging Cell,
9,
895-910.
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J.Wang,
T.R.Sarkar,
M.Zhou,
S.Sharan,
D.A.Ritt,
T.D.Veenstra,
D.K.Morrison,
A.M.Huang,
and
E.Sterneck
(2010).
CCAAT/enhancer binding protein delta (C/EBPdelta, CEBPD)-mediated nuclear import of FANCD2 by IPO4 augments cellular response to DNA damage.
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Proc Natl Acad Sci U S A,
107,
16131-16136.
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J.Xu,
A.T.De Jong,
G.Chen,
H.K.Chow,
C.O.Damaso,
A.Schwartz Mittelman,
and
J.A.Shin
(2010).
Reengineering natural design by rational design and in vivo library selection: the HLH subdomain in bHLHZ proteins is a unique requirement for DNA-binding function.
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Protein Eng Des Sel,
23,
337-346.
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K.Musunuru,
A.Strong,
M.Frank-Kamenetsky,
N.E.Lee,
T.Ahfeldt,
K.V.Sachs,
X.Li,
H.Li,
N.Kuperwasser,
V.M.Ruda,
J.P.Pirruccello,
B.Muchmore,
L.Prokunina-Olsson,
J.L.Hall,
E.E.Schadt,
C.R.Morales,
S.Lund-Katz,
M.C.Phillips,
J.Wong,
W.Cantley,
T.Racie,
K.G.Ejebe,
M.Orho-Melander,
O.Melander,
V.Koteliansky,
K.Fitzgerald,
R.M.Krauss,
C.A.Cowan,
S.Kathiresan,
and
D.J.Rader
(2010).
From noncoding variant to phenotype via SORT1 at the 1p13 cholesterol locus.
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Nature,
466,
714-719.
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K.Reckzeh,
and
J.Cammenga
(2010).
Molecular mechanisms underlying deregulation of C/EBPalpha in acute myeloid leukemia.
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Int J Hematol,
91,
557-568.
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K.Tsuchimochi,
M.Otero,
C.L.Dragomir,
D.A.Plumb,
L.F.Zerbini,
T.A.Libermann,
K.B.Marcu,
S.Komiya,
K.Ijiri,
and
M.B.Goldring
(2010).
GADD45beta enhances Col10a1 transcription via the MTK1/MKK3/6/p38 axis and activation of C/EBPbeta-TAD4 in terminally differentiating chondrocytes.
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J Biol Chem,
285,
8395-8407.
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K.Zaragoza,
V.Bégay,
A.Schuetz,
U.Heinemann,
and
A.Leutz
(2010).
Repression of transcriptional activity of C/EBPalpha by E2F-dimerization partner complexes.
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Mol Cell Biol,
30,
2293-2304.
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S.A.Pawar,
T.R.Sarkar,
K.Balamurugan,
S.Sharan,
J.Wang,
Y.Zhang,
S.F.Dowdy,
A.M.Huang,
and
E.Sterneck
(2010).
C/EBP{delta} targets cyclin D1 for proteasome-mediated degradation via induction of CDC27/APC3 expression.
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Proc Natl Acad Sci U S A,
107,
9210-9215.
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Y.Galon,
A.Finkler,
and
H.Fromm
(2010).
Calcium-regulated transcription in plants.
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Mol Plant,
3,
653-669.
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M.Miller
(2009).
The importance of being flexible: the case of basic region leucine zipper transcriptional regulators.
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Curr Protein Pept Sci,
10,
244-269.
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N.C.Liu,
W.J.Lin,
I.C.Yu,
H.Y.Lin,
S.Liu,
Y.F.Lee,
and
C.Chang
(2009).
Activation of TR4 orphan nuclear receptor gene promoter by cAMP/PKA and C/EBP signaling.
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Endocrine,
36,
211-217.
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S.Koschmieder,
B.Halmos,
E.Levantini,
and
D.G.Tenen
(2009).
Dysregulation of the C/EBPalpha differentiation pathway in human cancer.
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J Clin Oncol,
27,
619-628.
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T.M.Alleyne,
L.Peña-Castillo,
G.Badis,
S.Talukder,
M.F.Berger,
A.R.Gehrke,
A.A.Philippakis,
M.L.Bulyk,
Q.D.Morris,
and
T.R.Hughes
(2009).
Predicting the binding preference of transcription factors to individual DNA k-mers.
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Bioinformatics,
25,
1012-1018.
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T.V.Cohen,
K.D.Klarmann,
K.Sakchaisri,
J.P.Cooper,
D.Kuhns,
M.Anver,
P.F.Johnson,
S.C.Williams,
J.R.Keller,
and
C.L.Stewart
(2008).
The lamin B receptor under transcriptional control of C/EBPepsilon is required for morphological but not functional maturation of neutrophils.
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Hum Mol Genet,
17,
2921-2933.
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Z.Balazs,
R.A.Schweizer,
F.J.Frey,
F.Rohner-Jeanrenaud,
and
A.Odermatt
(2008).
DHEA induces 11 -HSD2 by acting on CCAAT/enhancer-binding proteins.
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J Am Soc Nephrol,
19,
92.
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A.D.Friedman
(2007).
Transcriptional control of granulocyte and monocyte development.
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Oncogene,
26,
6816-6828.
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A.Khanna-Gupta,
H.Sun,
T.Zibello,
H.M.Lee,
R.Dahl,
L.A.Boxer,
and
N.Berliner
(2007).
Growth factor independence-1 (Gfi-1) plays a role in mediating specific granule deficiency (SGD) in a patient lacking a gene-inactivating mutation in the C/EBPepsilon gene.
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Blood,
109,
4181-4190.
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G.D.Amoutzias,
E.Bornberg-Bauer,
S.G.Oliver,
and
D.L.Robertson
(2006).
Reduction/oxidation-phosphorylation control of DNA binding in the bZIP dimerization network.
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BMC Genomics,
7,
107.
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M.B.Schuster,
and
B.T.Porse
(2006).
C/EBPalpha: a tumour suppressor in multiple tissues?
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Biochim Biophys Acta,
1766,
88.
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P.Hatzis,
I.Kyrmizi,
and
I.Talianidis
(2006).
Mitogen-activated protein kinase-mediated disruption of enhancer-promoter communication inhibits hepatocyte nuclear factor 4alpha expression.
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Mol Cell Biol,
26,
7017-7029.
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Y.J.Lee,
L.C.Jones,
N.A.Timchenko,
D.Perrotti,
D.G.Tenen,
and
S.C.Kogan
(2006).
CCAAT/enhancer binding proteins alpha and epsilon cooperate with all-trans retinoic acid in therapy but differ in their antileukemic activities.
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Blood,
108,
2416-2419.
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F.Li,
D.A.Parry,
and
M.J.Scott
(2005).
The amino-terminal region of Drosophila MSL1 contains basic, glycine-rich, and leucine zipper-like motifs that promote X chromosome binding, self-association, and MSL2 binding, respectively.
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Mol Cell Biol,
25,
8913-8924.
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J.Al Sarraj,
C.Vinson,
J.Han,
and
G.Thiel
(2005).
Regulation of GTP cyclohydrolase I gene transcription by basic region leucine zipper transcription factors.
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J Cell Biochem,
96,
1003-1020.
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G.L.Wang,
P.Iakova,
M.Wilde,
S.Awad,
and
N.A.Timchenko
(2004).
Liver tumors escape negative control of proliferation via PI3K/Akt-mediated block of C/EBP alpha growth inhibitory activity.
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Genes Dev,
18,
912-925.
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The most recent references are shown first.
Citation data come partly from CiteXplore and partly
from an automated harvesting procedure. Note that this is likely to be
only a partial list as not all journals are covered by
either method. However, we are continually building up the citation data
so more and more references will be included with time.
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