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J Biol Chem, Vol. 275, Issue 12, 8263-8266, March 24, 2000
From the A number of second messenger pathways propagate
inductive signals via protein-protein interactions that are
phosphorylation-dependent. The second messenger, cAMP, for
example, promotes cellular gene expression via the protein kinase
A-mediated phosphorylation of cAMP-response element-binding protein
(CREB) at Ser133, and this modification in turn
stimulates the association of CREB with the co-activator, CREB-binding
protein (CBP). The solution structure of the CREB·CBP complex, using
relevant interaction domains, kinase inducible domain and
kinase-induced domain interacting domain, referred to as KID and KIX,
respectively, shows that KID undergoes a coil to helix transition, upon
binding to KIX, that stabilizes complex formation. Whether such changes
occur in the context of the full-length CREB and CBP proteins, however,
is unclear. Here we characterize a novel antiserum that specifically binds to the CREB·CBP complex but to neither protein individually. Epitope mapping experiments demonstrate that the CREB·CBP antiserum detects residues in KID that undergo a conformational change upon binding to KIX. The ability of this antiserum to recognize full-length CREB·CBP complexes in a
phospho-(Ser133)-dependent manner demonstrates
that the structural transition observed with the isolated KID domain
also occurs in the context of the full-length CREB protein. To our
knowledge, this is the first report documenting formation of endogenous
cellular protein-protein complexes in situ.
A number of signaling pathways modulate cellular gene expression
via the phosphorylation of specific nuclear factors. The second
messenger, cAMP, for example, promotes target gene expression via the
phosphorylation of CREB1 at
Ser133 (1). Although phosphorylation appears to enhance the
nuclear import, multimerization, or DNA binding activities of certain factors, CREB belongs to a group of activators whose trans-activation potential is specifically affected (2).
The CREB trans-activation domain is bipartite, consisting of
constitutive and inducible activators that function synergistically in
response to cAMP stimulation (2, 3). The constitutive glutamine-rich
activation domain, referred to as Q2, has been found to promote
transcription via an interaction with TFIID (4). By contrast, the
kinase inducible domain (KID) stimulates target gene expression,
following its phosphorylation at Ser133, by associating
with the KIX domain of the co-activator CBP (5-7). The solution
structure of the KID·KIX complex reveals that
Ser133-phosphorylated KID undergoes a random coil to helix
transition upon complex formation with KIX, and this transition in turn
stabilizes the interaction between CREB and CBP and its paralog P300
(8, 9).
In addition to cAMP, a wide variety of extracellular stimuli, including
phosphoinositol and calcium agonists as well as certain growth factors
such as nerve growth factor, epidermal growth factor, insulin-like
growth factor, and platelet-derived growth factor, appear to promote
Ser133 phosphorylation of CREB with high stoichiometry
(10-14). However, these pathways are unable to promote target gene
expression via CREB per se, reflecting a block either in
recruitment of CBP or in the subsequent assembly of the transcriptional
apparatus (10).
A number of methodologies, including co-immunoprecipitation (co-IP) and
fluorescence resonance energy transfer (FRET), have been employed to
evaluate protein-protein interactions (15). Such procedures are limited
by technical manipulations, such as protein extraction (co-IP) or
over-expression (FRET), that may influence the recovery or detection of
protein complexes.
Here we employ a novel complex-specific antiserum to monitor the
CREB·CBP interaction following exposure to various stimuli. Immunocytochemical experiments reveal that CREB·CBP complex
formation, in response to cAMP, is limited to discrete compartments
within the nucleus. Remarkably, other stimuli were found to have
distinct effects on complex formation, even in light of comparable
potency at the level of Ser133 phosphorylation. Our results
illustrate a novel mechanism for signal discrimination in the nucleus
at the level of co-activator recruitment.
Preparation of CREB·CBP-specific Antiserum--
KID and KIX
were expressed in Escherichia coli BL21 cells and
purified as described previously (8). The peptides were cross-linked with glutaraldehyde in cross-linking buffer (20 mM Hepes,
pH 7.5, 100 mM KCl, 2 mM MgCl2, 2 mM EDTA). For anti-KID·KIX ( Immunocytochemistry--
D5 cells were grown on glass coverslips
and stimulated with forskolin and isobutylmethylxanthine or TPA for 10 min. The cells were methanol-fixed at To evaluate CREB·CBP complex formation in vivo, we
developed a complex-specific antiserum using glutaraldehyde
cross-linked phospho-(Ser133) KID·KIX complexes as
immunogen. In Western blot assays, The KID domain is highly conserved among CREB family members,
particularly in residues that function in protein-protein interactions with KIX (8). In gel mobility shift assays, for example,
ACCELERATED PUBLICATION
Stimulus-specific Interaction between Activator-Coactivator
Cognates Revealed with a Novel Complex-specific Antiserum*
,¶
Peptide Biology Laboratories, Salk
Institute for Biological Studies, La Jolla, California 92037 and
§ Molecular Biology of the Cell I, Deutsches
Krebsforschungszentrum, Im Neuenheimerfeld 280, D-69120 Heidelberg,
Germany
ABSTRACT
TOP
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS
DISCUSSION
REFERENCES
INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS
DISCUSSION
REFERENCES
EXPERIMENTAL PROCEDURES
TOP
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS
DISCUSSION
REFERENCES
KK) antiserum, IgG was
purified by 50% ammonium sulfate precipitation followed by protein
A-agarose affinity purification. Antibodies to phosphoKID or KIX alone
were preabsorbed by incubation with a phosphoKID and KIX-coupled
Affi-Gel 10 resins individually. KID·KIX complex-specific antibodies
were then purified by incubating with a phosphoKID·KIX-coupled Affi-Gel 10 resin and eluting with 100 mM glycine. For
CREB/p300 co-immunoprecipitations, 100 ng of recombinant p300 (gift
from P. Nakatani, Dana Farber Cancer Center) and 2 µg of recombinant CREB or phospho-(Ser133) CREB were co-incubated, and the
immunoprecipitates were processed as described previously (16). Gel
shift assays with 32P-labeled CRE or GAL4 response element
oligonucleotides were performed as reported (1).
10 °C for 5 min followed by
three 5-min washes in PBS. Cells were blocked for 30 min with 3% BSA
in PBS and donkey serum diluted 1:50. Primary antibodies were diluted in 3% BSA/PBS to 1:2000 for the phosphoCREB-specific antibody 5322 or
1:100 (3 µg/ml) for the KID·KIX-specific antibody. The cells were
incubated with the primary antibodies for 1 h at room temperature,
followed by 3 washes with PBS and a 1-h incubation with
biotin-conjugated donkey anti-rabbit IgG diluted 1:200 in 3% BSA/PBS.
After 3 washes in PBS, Texas Red-conjugated streptavidin was added at
1:200 dilution in 3% BSA/PBS. After a 1-h incubation, cells were
washed 3 times in PBS and mounted in 90% glycerol/PBS containing 1 mg/ml phenylenediamine.
RESULTS
TOP
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS
DISCUSSION
REFERENCES
KK antiserum was initially purified from crude serum of
immunized rabbits by chromatography over separate KID and KIX resins to
remove antibodies that could recognize either
phospho-(Ser133) KID or KIX peptides independently (Fig.
1A). Flow-through fractions from these columns were then passed over resin containing cross-linked KID·KIX peptides, and the bound antibody fraction, referred to as
KK antiserum, was acid eluted.
View larger version (29K):
[in a new window]
Fig. 1.
Characterization of a CREB·CBP
complex-specific antiserum. A, recombinant
phospho-(Ser133) KID (P-KID; lane 1)
and KIX (lane 2) peptides from CREB and CBP, respectively,
were cross-linked with glutaraldehyde (PKID/KIX; lane
3) and then employed as immunogen to generate KID·KIX-specific
antisera. B, Western blot assay of
phospho-(Ser133) KID, KIX, and phospho-(Ser133)
KID·KIX complexes using affinity-purified KID·KIX-specific
antiserum ( KK). C, top panel, Western
blot assay of P300 recovered from KK immunoprecipitates following
incubation of antiserum with purified full-length P300 (lane
2), P300 plus unphosphorylated CREB (lane 3), or P300
plus phospho-(Ser133) CREB (P-CREB; lane
4). Western blot assay was performed with anti-P300 antiserum.
Input, 50% of total P300 protein was added to each immunoprecipitation
reaction. Bottom panel, autoradiogram of in
vitro-translated 35S-CBP following co-incubation with
KK alone (lane 2), unphosphorylated CREM (lane
3), or protein kinase A-phosphorylated CREM (lane 4).
Lane 1, 20% of onput shown.
KK antiserum could recognize cross-linked
KID·KIX complexes but not KIX or phospho-(Ser133) KID
peptides alone (Fig. 1B). Consistent with the notion that KK antiserum is also competent to detect complex formation between full-length phospho-(Ser133) CREB and CBP/P300 proteins,
P300 was recovered from immunoprecipitates of recombinant P300 and
phospho-(Ser133) CREB but not of P300 plus unphosphorylated
CREB (Fig. 1C, top panel). KK antiserum also
detected the phospho-(Ser133)-dependent
recruitment of CBP in immunoprecipitation assays, demonstrating the
capacity of this antiserum to recognize complexes formed with both
co-activators (Fig. 1C, bottom panel).
KK antiserum was also capable of binding to KIX complexes formed with the
mammalian CREB homolog, CREM, but not with the more distantly related
Caenorhabditis elegans CREB polypeptide
(eCREB)2 (Fig.
2A). Compared with its
mammalian counterpart, eCREB contains a number of amino acid
substitutions within its KID domain (amino acids 40-65) (Fig.
2B), prompting us to evaluate which of these constituted an
important epitope for KK recognition.
View larger version (38K):
[in a new window]
Fig. 2.
CREB·CBP-specific antiserum recognizes a
conformational change in CREB that accompanies complex formation.
A, gel mobility shift assay of C. elegans
phospho-(Ser54) CREB (eP-CREB; lanes
1-5) and murine phospho-(Ser71) CREM (Mouse
P-CREM; lanes 6-9) using 32P-labeled CRE
oligonucleotide. Reactions contained either eCREB or CREM plus KIX,
KK antiserum, or -phosphospecific CREB antiserum indicated by
plus signs over each lane. Bands in
lanes 1 and 6 represent 32P-labeled
phosphorylated eCREB·CRE and CREM·CRE complexes alone,
respectively. B, sequence of homologous A and B
regions in the KID domains of C. elegans CREB, mouse CREM,
and rat CREB. Amino acid differences are shown in bold.
C. gel mobility shift assay of wild-type and
mutant (WT and M1, M2, and
M3, respectively) GAL4-KID polypeptides using
double-stranded GAL4-binding site oligonucleotide. Relative migration
of GAL4-KID (P-KID), GAL4-KID·KIX (pKID·KIX),
and KK supershifted (Ab:KID·KIX) complexes bound to the
32P-labeled GAL4 oligonucleotide is shown. Addition of KIX
or KK antiserum (KID·KIX) to reactions is indicated
by plus signs over each lane.
D, ribbon diagram showing solution structure of
KID·KIX complex. The KID domain is shown in yellow and the
KIX domain is shown in cyan. The relative positions of
residues important for KK recognition (K136 and
N139) on the B helix are indicated. Reactions containing
eP-CREB or Mouse-P-CREM indicated by
lines over lanes.
Mutation of residues 121-123 (M1) in the A region of rat CREB
(amino acids 121-129) to corresponding amino acids of C. elegans CREB had no effect on either complex formation with KIX or
recognition by KK by gel shift assay (Fig. 2, B and
C; compare WT and M1). Mutation of
residues 127 and 129 (M2) or 136 and 139 (M3) in KID partially
disrupted interaction with KIX by gel shift assay (Fig. 2, B
and C; compare WT, M2, and
M3). Although these residues do not appear to form surface
contacts with KIX (8), mutation at these amino acids may impose
structural constraints on the mutant KID peptides that make complex
formation less favorable. Nevertheless, complexes formed with mutant M2
KID were supershifted by KK antiserum, but complexes formed with
mutant M3 KID containing Lys136 
Met and
Asn139 Lys substitutions in the B region were not
(Fig. 2C; compare WT, M2, and
M3). Taken together, these results indicate that residues Lys136 and Asn139 are critical for recognition
by KK antiserum.
Lys136 and Asn139 are directly aligned on the
solvent face of helix B, a region in KID that undergoes a random
coil to helix transition upon complex formation with KIX (Fig.
2D). The importance of these residues for recognition by
KK suggests that the antiserum detects, in part, the conformational
change in KID that accompanies complex formation with KIX. Moreover,
the ability of KK to recognize full-length CREB·CBP complexes
suggests that the structural change detected by NMR analysis with KID
and KIX peptides also occurs in the context of the full-length proteins.
In addition to cAMP, other stimuli such as the phorbol ester TPA can
promote Ser133 phosphorylation of CREB, yet these stimuli
are unable to induce target gene activation via CBP, reflecting a block
either in CREB·CBP complex formation or in the subsequent recruitment
of the transcriptional apparatus. To evaluate formation of CREB·CBP
complexes in vivo, we employed NIH 3T3 cells expressing
chromosomal copies of the rat somatostatin gene, hereafter referred to
as D5 cells (17). Treating D5 cells with TPA induced Ser133
phosphorylation of CREB with comparable stoichiometry to forskolin by
Western blot assay with phospho-specific CREB antiserum 5322 (Fig.
3A). Forskolin stimulated
somatostatin mRNA accumulation 5-fold in D5 cells, whereas TPA had
no discernible effect (Fig. 3B).
|
Consistent with the absence of phospho-(Ser133) CREB
staining under basal conditions, no CREB·CBP complexes were detected
in untreated D5 cells by immunofluorescence analysis with KK
antiserum (Fig. 4). Treatment with
forskolin induced accumulation of phospho-(Ser133) CREB and
correspondingly promoted the appearance of CREB·CBP complexes (Fig.
4A). By contrast with forskolin, however, no CREB·CBP complexes were detected in TPA-treated cells despite comparable levels
of Ser133 phosphorylation.
|
To confirm the specificity of the KK antiserum, we employed
fibroblasts from CREB / mice (18). Compared with cells from wild-type littermates, which showed abundant nuclear staining following
treatment with cAMP agonist, only background cytoplasmic staining was
observed in CREB / cells (Fig. 4B). These results demonstrate that CREB is indeed an important epitope for recognition by
KK antibody. Under higher magnification, a punctate staining pattern
was noted with KK antiserum in forskolin-stimulated cells, suggesting that CREB·CBP complexes are formed in discrete loci within
the nucleus (Fig. 4C).
| |
DISCUSSION |
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|
TOP
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS
DISCUSSION
REFERENCES
|
|---|
Our results illustrate a novel approach to the study of cellular
signaling; to our knowledge, this is the first report documenting the
formation of nuclear protein-protein complexes in situ.
KK antiserum binds in part to residues in KID that undergo a
conformational change following complex formation with KIX. The ability
of KK antiserum to recognize full-length CREB·CBP complexes
strongly supports the notion that this helical transition also occurs
within the context of the full-length CREB protein. Structural
transitions in transcription activators like CREB may therefore be
integral to the process of recruiting the transcriptional machinery.
Other complex-specific antisera have been described, most notably against human immunodeficiency virus gp120 bound to its cellular receptor, CD4 (19-21). gp120 appears to undergo a conformational change, upon binding to CD4, that exposes an epitope for recognition by complex-specific antiserum. Indeed, a number of proteins appear to undergo structural changes upon complex formation with their cognate receptor or co-activator (22), suggesting that the development of complex-specific antisera may be generally useful for studies of cellular signaling.
CREB·CBP complexes appear to be formed at discrete regions within the nucleus. Although the constituents of these speckles are unknown aside from CREB and CBP, it is tempting to speculate that they may contain other components of the transcriptional apparatus. In this regard, CBP has been found to associate with RNA polymerase II holoenzyme complexes (23-25) as well as promyelocytic protein-containing nuclear bodies (26). Further analyses with appropriate antisera may reveal which of these complexes is recruited to CREB in response to cAMP but not other signaling pathways.
The ability of KK antiserum to distinguish between different
signaling pathways demonstrates the utility of this reagent in
monitoring cellular activity compared with phospho-(Ser133)
CREB antiserum. PhosphoCREB-specific antisera have been widely used,
particularly in neuronal cells, to evaluate cellular responses to
various stimuli. Our data suggest that some subset of these signals may
not elicit a transcriptional response, at least via the same pathway as cAMP.
Phosphorylation of CREB in response to TPA is likely to be indirect and
likely to involve extracellular signal-regulated kinases 1 and 2 and
pp90RSK. Activation of the mitogen-activated protein kinase
pathway may inhibit CREB·CBP complex formation by inducing phosphorylation of CREB at other inhibitory sites. In this regard, phosphorylation of CREB at Ser142 has been shown to block
target gene activation in part by blocking CREB·CBP complex formation
(9, 27). It will be of interest to determine the mechanism by which
CREB discriminates between cAMP and other second messenger pathways.
| |
ACKNOWLEDGEMENTS |
|---|
We thank Ulupi Jhala, David Parker, Joan Vaughan, and Wylie Vale for help with antibody preparation. We also thank Hiroshi Asahara for help with C. elegans CREB experiments.
| |
FOOTNOTES |
|---|
* This work was supported by National Institutes of Health Grants RO1-GM37828 and F32-DK09806.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
¶ To whom correspondence should be addressed. Tel.: 619-453-4100 (ext. 1107); Fax: 619-552-1546; E-mail: Montminy@Salk.edu.
2 M. Montminy, manuscript in preparation.
| |
ABBREVIATIONS |
|---|
The abbreviations used are:
CREB, cAMP-response
element-binding protein;
KID, kinase inducible domain;
KIX, kinase-inducible domain interacting domain;
CBP, CREB-binding protein;
co-IP, co-immunoprecipitation;
FRET, fluorescence resonance energy
transfer;
KK, anti-KID·KIX;
CRE, cAMP-response element;
TPA, 12-O-tetradecanoylphorbol-13-acetate;
PBS, phosphate-buffered saline;
BSA, bovine serum albumin;
CREM, mammalian
CREB homolog;
eCREB, Caenorhabditis elegans CREB
polypeptide.
| |
REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS
DISCUSSION
REFERENCES
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