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PDBsum entry 1bu9
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Hormone/growth factor
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PDB id
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1bu9
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Contents |
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* Residue conservation analysis
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DOI no:
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Biochemistry
38:2930-2940
(1999)
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PubMed id:
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Tumor suppressor INK4: determination of the solution structure of p18INK4C and demonstration of the functional significance of loops in p18INK4C and p16INK4A.
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J.Li,
I.J.Byeon,
K.Ericson,
M.J.Poi,
P.O'Maille,
T.Selby,
M.D.Tsai.
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ABSTRACT
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Since the structures of several ankyrin-repeat proteins including the INK4
(inhibitor of cyclin-dependent kinase 4) family have been reported recently, the
detailed structures and the functional roles of the loops have drawn
considerable interest. This paper addresses the potential importance of the
loops of ankyrin-repeat proteins in three aspects. First, the solution structure
of p18INK4C was determined by NMR, and the loop structures were analyzed in
detail. The loops adapt nascent antiparallel beta-sheet structures, but the
positions are slightly different from those in the crystal structure. A detailed
comparison between the solution structures of p16 and p18 has also been
presented. The determination of the p18 solution structure made such detailed
comparisons possible for the first time. Second, the [1H,15N]HSQC NMR experiment
was used to probe the interactions between p18INK4C and other proteins. The
results suggest that p18INK4C interacts very weakly with dna K and glutathione
S-transferase via the loops. The third aspect employed site-specific mutagenesis
and functional assays. Three mutants of p18 and 11 mutants of p16 were
constructed to test functional importance of loops and helices. The results
suggest that loop 2 is likely to be part of the recognition surface of p18INK4C
or p16INK4A for CDK4, and they provide quantitative functional contributions of
specific residues. Overall, our results enhance understanding of the structural
and functional roles of the loops in INK4 tumor suppressors in particular and in
ankyrin-repeat proteins in general.
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Literature references that cite this PDB file's key reference
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Google scholar
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PubMed id
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Reference
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N.Fahham,
S.Sardari,
S.N.Ostad,
B.Vaziri,
and
M.H.Ghahremani
(2010).
C-terminal domain of p16(INK4a) is adequate in inducing cell cycle arrest, growth inhibition and CDK4/6 interaction similar to the full length protein in HT-1080 fibrosarcoma cells.
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J Cell Biochem,
111,
1598-1606.
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C.F.Cervantes,
P.R.Markwick,
S.C.Sue,
J.A.McCammon,
H.J.Dyson,
and
E.A.Komives
(2009).
Functional dynamics of the folded ankyrin repeats of I kappa B alpha revealed by nuclear magnetic resonance.
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Biochemistry,
48,
8023-8031.
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J.Aguirre-Hernández,
B.S.Milne,
C.Queen,
P.C.O'Brien,
T.Hoather,
S.Haugland,
M.A.Ferguson-Smith,
J.M.Dobson,
and
D.R.Sargan
(2009).
Disruption of chromosome 11 in canine fibrosarcomas highlights an unusual variability of CDKN2B in dogs.
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BMC Vet Res,
5,
27.
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W.van Veelen,
R.Klompmaker,
M.Gloerich,
C.J.van Gasteren,
E.Kalkhoven,
R.Berger,
C.J.Lips,
R.H.Medema,
J.W.Höppener,
and
D.S.Acton
(2009).
P18 is a tumor suppressor gene involved in human medullary thyroid carcinoma and pheochromocytoma development.
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Int J Cancer,
124,
339-345.
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A.Mahajan,
Y.Guo,
C.Yuan,
C.M.Weghorst,
M.D.Tsai,
and
J.Li
(2007).
Dissection of protein-protein interaction and CDK4 inhibition in the oncogenic versus tumor suppressing functions of gankyrin and P16.
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J Mol Biol,
373,
990.
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F.Wang,
J.Hu,
P.Song,
and
W.Gong
(2007).
Two novel transcripts encoding two Ankyrin repeat containing proteins have preponderant expression during the mouse spermatogenesis.
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Mol Biol Rep,
34,
249-260.
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Y.C.Lin,
M.B.Diccianni,
Y.Kim,
H.H.Lin,
C.H.Lee,
R.J.Lin,
S.H.Joo,
J.Li,
T.J.Chuang,
A.S.Yang,
H.H.Kuo,
M.D.Tsai,
and
A.L.Yu
(2007).
Human p16gamma, a novel transcriptional variant of p16(INK4A), coexpresses with p16(INK4A) in cancer cells and inhibits cell-cycle progression.
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Oncogene,
26,
7017-7027.
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G.Interlandi,
G.Settanni,
and
A.Caflisch
(2006).
Unfolding transition state and intermediates of the tumor suppressor p16INK4a investigated by molecular dynamics simulations.
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Proteins,
64,
178-192.
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J.Sridhar,
N.Akula,
and
N.Pattabiraman
(2006).
Selectivity and potency of cyclin-dependent kinase inhibitors.
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AAPS J,
8,
E204-E221.
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C.H.Croy,
S.Bergqvist,
T.Huxford,
G.Ghosh,
and
E.A.Komives
(2004).
Biophysical characterization of the free IkappaBalpha ankyrin repeat domain in solution.
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Protein Sci,
13,
1767-1777.
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K.S.Tang,
A.R.Fersht,
and
L.S.Itzhaki
(2003).
Sequential unfolding of ankyrin repeats in tumor suppressor p16.
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Structure,
11,
67-73.
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J.Li,
and
M.D.Tsai
(2002).
Novel insights into the INK4-CDK4/6-Rb pathway: counter action of gankyrin against INK4 proteins regulates the CDK4-mediated phosphorylation of Rb.
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Biochemistry,
41,
3977-3983.
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M.J.Poi,
T.Yen,
J.Li,
H.Song,
J.C.Lang,
D.E.Schuller,
D.K.Pearl,
B.C.Casto,
M.D.Tsai,
and
C.M.Weghorst
(2001).
Somatic INK4a-ARF locus mutations: a significant mechanism of gene inactivation in squamous cell carcinomas of the head and neck.
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Mol Carcinog,
30,
26-36.
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C.Yuan,
T.L.Selby,
J.Li,
I.J.Byeon,
and
M.D.Tsai
(2000).
Tumor suppressor INK4: refinement of p16INK4A structure and determination of p15INK4B structure by comparative modeling and NMR data.
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Protein Sci,
9,
1120-1128.
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PDB code:
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J.Li,
M.J.Poi,
D.Qin,
T.L.Selby,
I.J.Byeon,
and
M.D.Tsai
(2000).
Tumor suppressor INK4: quantitative structure-function analyses of p18INK4C as an inhibitor of cyclin-dependent kinase 4.
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Biochemistry,
39,
649-657.
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J.A.Endicott,
M.E.Noble,
and
J.A.Tucker
(1999).
Cyclin-dependent kinases: inhibition and substrate recognition.
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Curr Opin Struct Biol,
9,
738-744.
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S.G.Sedgwick,
and
S.J.Smerdon
(1999).
The ankyrin repeat: a diversity of interactions on a common structural framework.
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Trends Biochem Sci,
24,
311-316.
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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.
Where a reference describes a PDB structure, the PDB
code is
shown on the right.
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Links
