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* Residue conservation analysis
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DOI no:
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Nature
391:859-865
(1998)
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PubMed id:
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Structure of the retinoblastoma tumour-suppressor pocket domain bound to a peptide from HPV E7.
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J.O.Lee,
A.A.Russo,
N.P.Pavletich.
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ABSTRACT
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The pocket domain of the retinoblastoma (Rb) tumour suppressor is central to Rb
function, and is frequently inactivated by the binding of the human papilloma
virus E7 oncoprotein in cervical cancer. The crystal structure of the Rb pocket
bound to a nine-residue E7 peptide containing the LxCxE motif, shared by other
Rb-binding viral and cellular proteins, shows that the LxCxE peptide binds a
highly conserved groove on the B-box portion of the pocket; the A-box portion
appears to be required for the stable folding of the B box. Also highly
conserved is the extensive A-B interface, suggesting that it may be an
additional protein-binding site. The A and B boxes each contain the cyclin-fold
structural motif, with the LxCxE-binding site on the B-box cyclin fold being
similar to a Cdk2-binding site of cyclin A and to a TBP-binding site of TFIIB.
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Selected figure(s)
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Figure 3.
Figure 3 The A-B interface is like a folded structural
domain, and is highly conserved. a, Residues that form the
hydrophobic core of the interface. b, c, Two regions with
notable hydrogen-bond networks involving both side-chain and
backbone groups. Hydrogen bonds are indicated by yellow dotted
lines. The importance of the interface is underscored by the
presence of tumour-derived mutations that target residues either
in the hydrophobic core or in the hydrogen-bond networks. d, The
surface of the pocket is coloured according to residue identity
across the Rb homologues of five species and the p107 and p130
family members (Fig. 2a). Dark green indicates identities and
white non-conserved residues. This view highlights the striking
conservation of residues that are on a surface patch about
halfway around the A-B interface.
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Figure 4.
Figure 4 The E7 LxCxE binds as an extended peptide onto a
conserved groove of the B box. a, Hydrogen-bond interactions to
peptide backbone groups and theGlu 26 side chain, indicated as
red dotted lines, cover the length of the peptide. b, The E7 Leu
22, Cys 24 and Leu 28 side chains bind in small hydrophobic
pockets. c, The surface of the B box is coloured according to
residue identity as in Fig. 3d, highlighting the striking
conservation of residues that make up the LxCxE binding site. d,
The clustering of basic residues at the rim of the LxCxE binding
site, a well-conserved feature, may facilitate the binding of
viral oncogenes that often have a stretch of acidic residues
following the LxCxE motif. Note the conserved clustering of
acidic residues at the opposite side of the binding site.
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The above figures are
reprinted
by permission from Macmillan Publishers Ltd:
Nature
(1998,
391,
859-865)
copyright 1998.
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Figures were
selected
by the author.
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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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PDB code:
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PDB code:
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PDB code:
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Oncogene, 25,
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Oncogene, 25,
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Invest Ophthalmol Vis Sci, 47,
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J Virol Methods, 134,
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Oncogene, 25,
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PDB codes:
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Cancer Res, 66,
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PDB code:
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A.Ledl,
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EMBO J, 24,
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PDB code:
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Cell, 123,
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PDB code:
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S.O.Jung,
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Proc Natl Acad Sci U S A, 102,
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X-ray structure of human gankyrin, the product of a gene linked to hepatocellular carcinoma.
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| |
Proteins, 55,
214-217.
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PDB code:
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N.Adachi,
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J Biol Chem, 279,
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PDB code:
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G.Arguello-Astorga,
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A novel motif in geminivirus replication proteins interacts with the plant retinoblastoma-related protein.
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Distinct mechanisms for repression of RNA polymerase III transcription by the retinoblastoma tumor suppressor protein.
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J.Alonso,
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Two independent RB1-inactivating mutations in peripheral blood DNA of a hereditary retinoblastoma patient.
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Genes Chromosomes Cancer, 40,
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M.J.Dubin,
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E.Y.Sum,
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V.A.Valova,
P.J.Robinson,
G.J.Lindeman,
J.N.Glover,
J.E.Visvader,
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Dimerization of CtIP, a BRCA1- and CtBP-interacting protein, is mediated by an N-terminal coiled-coil motif.
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J Biol Chem, 279,
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Docking-dependent regulation of the Rb tumor suppressor protein by Cdk4.
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Mol Cell Biol, 24,
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S.Krzywda,
A.M.Brzozowski,
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The crystal structure of gankyrin, an oncoprotein found in complexes with cyclin-dependent kinase 4, a 19 S proteasomal ATPase regulator, and the tumor suppressors Rb and p53.
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J Biol Chem, 279,
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PDB code:
|
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|
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|
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|
V.Pennaneach,
V.Barbier,
K.Regazzoni,
R.Fotedar,
and
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Rb inhibits E2F-1-induced cell death in a LXCXE-dependent manner by active repression.
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J Biol Chem, 279,
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Y.W.Chen,
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and
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The structure of the AXH domain of spinocerebellar ataxin-1.
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J Biol Chem, 279,
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PDB code:
|
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|
|
|
|
|
|
B.Xiao,
J.Spencer,
A.Clements,
N.Ali-Khan,
S.Mittnacht,
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Crystal structure of the retinoblastoma tumor suppressor protein bound to E2F and the molecular basis of its regulation.
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| |
Proc Natl Acad Sci U S A, 100,
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PDB code:
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D.Ma,
P.Zhou,
and
J.W.Harbour
(2003).
Distinct mechanisms for regulating the tumor suppressor and antiapoptotic functions of Rb.
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J Biol Chem, 278,
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J Cell Physiol, 197,
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J.H.Jeon,
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Transglutaminase 2 inhibits Rb binding of human papillomavirus E7 by incorporating polyamine.
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EMBO J, 22,
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Proc Natl Acad Sci U S A, 100,
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Clefts, grooves, and (small) pockets: the structure of the retinoblastoma tumor suppressor in complex with its cellular target E2F unveiled.
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Proc Natl Acad Sci U S A, 100,
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Am J Hum Genet, 72,
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J Biol Chem, 278,
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Stat Med, 21,
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Retinoblastoma protein-mediated apoptosis after gamma-irradiation.
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J Biol Chem, 277,
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Structural basis for the recognition of the E2F transactivation domain by the retinoblastoma tumor suppressor.
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| |
Genes Dev, 16,
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|
PDB code:
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|
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|
|
|
|
|
C.S.Sullivan,
and
J.M.Pipas
(2002).
T antigens of simian virus 40: molecular chaperones for viral replication and tumorigenesis.
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Microbiol Mol Biol Rev, 66,
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F.A.Dick,
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Three regions of the pRB pocket domain affect its inactivation by human papillomavirus E7 proteins.
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| |
J Virol, 76,
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G.T.Kim,
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T.Tsuge,
K.H.Cho,
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R.Yokoyama,
K.Nishitani,
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The ANGUSTIFOLIA gene of Arabidopsis, a plant CtBP gene, regulates leaf-cell expansion, the arrangement of cortical microtubules in leaf cells and expression of a gene involved in cell-wall formation.
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EMBO J, 21,
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Tumor suppression by a severely truncated species of retinoblastoma protein.
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| |
Mol Cell Biol, 22,
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M.Classon,
and
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The retinoblastoma tumour suppressor in development and cancer.
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Nat Rev Cancer, 2,
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The retinoblastoma family: twins or distant cousins?
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| |
Genome Biol, 3,
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S.Ansieau,
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The conserved Mynd domain of BS69 binds cellular and oncoviral proteins through a common PXLXP motif.
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J Biol Chem, 277,
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T.Farkas,
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K.Holm,
J.Lukas,
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Distinct phosphorylation events regulate p130- and p107-mediated repression of E2F-4.
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J Biol Chem, 277,
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T.Tonini,
C.Hillson,
and
P.P.Claudio
(2002).
Interview with the retinoblastoma family members: do they help each other?
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| |
J Cell Physiol, 192,
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V.D.Brown,
and
B.L.Gallie
(2002).
The B-domain lysine patch of pRB is required for binding to large T antigen and release of E2F by phosphorylation.
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| |
Mol Cell Biol, 22,
1390-1401.
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A.M.Helt,
and
D.A.Galloway
(2001).
Destabilization of the retinoblastoma tumor suppressor by human papillomavirus type 16 E7 is not sufficient to overcome cell cycle arrest in human keratinocytes.
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| |
J Virol, 75,
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F.X.Wilson
(2001).
Emerging therapies for human papillomavirus infection.
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| |
Expert Opin Emerg Drugs, 6,
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H.Y.Kim,
B.Y.Ahn,
and
Y.Cho
(2001).
Structural basis for the inactivation of retinoblastoma tumor suppressor by SV40 large T antigen.
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| |
EMBO J, 20,
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|
|
PDB code:
|
|
|
|
|
|
|
|
J.Alonso,
P.García-Miguel,
J.Abelairas,
M.Mendiola,
E.Sarret,
M.T.Vendrell,
A.Navajas,
and
A.Pestaña
(2001).
Spectrum of germline RB1 gene mutations in Spanish retinoblastoma patients: Phenotypic and molecular epidemiological implications.
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| |
Hum Mutat, 17,
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J.G.Umen,
and
U.W.Goodenough
(2001).
Control of cell division by a retinoblastoma protein homolog in Chlamydomonas.
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| |
Genes Dev, 15,
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K.Hansen,
T.Farkas,
J.Lukas,
K.Holm,
L.Rönnstrand,
and
J.Bartek
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Phosphorylation-dependent and -independent functions of p130 cooperate to evoke a sustained G1 block.
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| |
EMBO J, 20,
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P.D.Adams
(2001).
Regulation of the retinoblastoma tumor suppressor protein by cyclin/cdks.
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| |
Biochim Biophys Acta, 1471,
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V.Pennaneach,
I.Salles-Passador,
A.Munshi,
H.Brickner,
K.Regazzoni,
F.Dick,
N.Dyson,
T.T.Chen,
J.Y.Wang,
R.Fotedar,
and
A.Fotedar
(2001).
The large subunit of replication factor C promotes cell survival after DNA damage in an LxCxE motif- and Rb-dependent manner.
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Mol Cell, 7,
715-727.
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A.Clements,
K.Johnston,
J.M.Mazzarelli,
R.P.Ricciardi,
and
R.Marmorstein
(2000).
Oligomerization properties of the viral oncoproteins adenovirus E1A and human papillomavirus E7 and their complexes with the retinoblastoma protein.
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| |
Biochemistry, 39,
16033-16045.
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A.Dahiya,
M.R.Gavin,
R.X.Luo,
and
D.C.Dean
(2000).
Role of the LXCXE binding site in Rb function.
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| |
Mol Cell Biol, 20,
6799-6805.
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|
A.Meléndez,
and
I.Greenwald
(2000).
Caenorhabditis elegans lin-13, a member of the LIN-35 Rb class of genes involved in vulval development, encodes a protein with zinc fingers and an LXCXE motif.
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| |
Genetics, 155,
1127-1137.
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D.DiCiommo,
B.L.Gallie,
and
R.Bremner
(2000).
Retinoblastoma: the disease, gene and protein provide critical leads to understand cancer.
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| |
Semin Cancer Biol, 10,
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|
F.A.Dick,
E.Sailhamer,
and
N.J.Dyson
(2000).
Mutagenesis of the pRB pocket reveals that cell cycle arrest functions are separable from binding to viral oncoproteins.
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| |
Mol Cell Biol, 20,
3715-3727.
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|
L.J.Kong,
B.M.Orozco,
J.L.Roe,
S.Nagar,
S.Ou,
H.S.Feiler,
T.Durfee,
A.B.Miller,
W.Gruissem,
D.Robertson,
and
L.Hanley-Bowdoin
(2000).
A geminivirus replication protein interacts with the retinoblastoma protein through a novel domain to determine symptoms and tissue specificity of infection in plants.
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| |
EMBO J, 19,
3485-3495.
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M.E.Hagensee
(2000).
Infection with Human Papillomavirus: Update on Epidemiology, Diagnosis, and Treatment.
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Curr Infect Dis Rep, 2,
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S.Miyake,
W.R.Sellers,
M.Safran,
X.Li,
W.Zhao,
S.R.Grossman,
J.Gan,
J.A.DeCaprio,
P.D.Adams,
and
W.G.Kaelin
(2000).
Cells degrade a novel inhibitor of differentiation with E1A-like properties upon exiting the cell cycle.
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| |
Mol Cell Biol, 20,
8889-8902.
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S.Park,
M.Uesugi,
and
G.L.Verdine
(2000).
A second calcineurin binding site on the NFAT regulatory domain.
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| |
Proc Natl Acad Sci U S A, 97,
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T.T.Chen,
and
J.Y.Wang
(2000).
Establishment of irreversible growth arrest in myogenic differentiation requires the RB LXCXE-binding function.
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| |
Mol Cell Biol, 20,
5571-5580.
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A.Brehm,
K.Ohbo,
W.Zwerschke,
V.Botquin,
P.Jansen-Dürr,
and
H.R.Schöler
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Synergism with germ line transcription factor Oct-4: viral oncoproteins share the ability to mimic a stem cell-specific activity.
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| |
Mol Cell Biol, 19,
2635-2643.
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A.Brehm,
and
T.Kouzarides
(1999).
Retinoblastoma protein meets chromatin.
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| |
Trends Biochem Sci, 24,
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A.Lai,
J.M.Lee,
W.M.Yang,
J.A.DeCaprio,
W.G.Kaelin,
E.Seto,
and
P.E.Branton
(1999).
RBP1 recruits both histone deacetylase-dependent and -independent repression activities to retinoblastoma family proteins.
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| |
Mol Cell Biol, 19,
6632-6641.
|
|
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C.Cenciarelli,
F.De Santa,
P.L.Puri,
E.Mattei,
L.Ricci,
F.Bucci,
A.Felsani,
and
M.Caruso
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Critical role played by cyclin D3 in the MyoD-mediated arrest of cell cycle during myoblast differentiation.
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| |
Mol Cell Biol, 19,
5203-5217.
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G.A.Otterson,
S.Modi,
K.Nguyen,
A.B.Coxon,
and
F.J.Kaye
(1999).
Temperature-sensitive RB mutations linked to incomplete penetrance of familial retinoblastoma in 12 families.
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| |
Am J Hum Genet, 65,
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H.Nakagami,
M.Sekine,
H.Murakami,
and
A.Shinmyo
(1999).
Tobacco retinoblastoma-related protein phosphorylated by a distinct cyclin-dependent kinase complex with Cdc2/cyclin D in vitro.
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| |
Plant J, 18,
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J.A.Endicott,
M.E.Noble,
and
J.A.Tucker
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Cyclin-dependent kinases: inhibition and substrate recognition.
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Curr Opin Struct Biol, 9,
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J.E.Sutcliffe,
C.A.Cairns,
A.McLees,
S.J.Allison,
K.Tosh,
and
R.J.White
(1999).
RNA polymerase III transcription factor IIIB is a target for repression by pocket proteins p107 and p130.
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| |
Mol Cell Biol, 19,
4255-4261.
|
|
|
|
|
|
|
J.L.Siegert,
and
P.D.Robbins
(1999).
Rb inhibits the intrinsic kinase activity of TATA-binding protein-associated factor TAFII250.
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| |
Mol Cell Biol, 19,
846-854.
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|
|
J.W.Harbour,
R.X.Luo,
A.Dei Santi,
A.A.Postigo,
and
D.C.Dean
(1999).
Cdk phosphorylation triggers sequential intramolecular interactions that progressively block Rb functions as cells move through G1.
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| |
Cell, 98,
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K.Macleod
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pRb and E2f-1 in mouse development and tumorigenesis.
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Curr Opin Genet Dev, 9,
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K.W.Kohn
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Molecular interaction map of the mammalian cell cycle control and DNA repair systems.
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| |
Mol Biol Cell, 10,
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M.L.Gillison,
W.M.Koch,
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K.V.Shah
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Human papillomavirus in head and neck squamous cell carcinoma: are some head and neck cancers a sexually transmitted disease?
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R.Schleif
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V.D.Brown,
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Cumulative effect of phosphorylation of pRB on regulation of E2F activity.
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| |
Mol Cell Biol, 19,
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W.G.Kaelin
(1999).
Functions of the retinoblastoma protein.
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Bioessays, 21,
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C.Gutierrez
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The retinoblastoma pathway in plant cell cycle and development.
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H.Su,
R.Baskaran,
E.S.Knudsen,
and
J.Y.Wang
(1998).
Growth suppression by an E2F-binding-defective retinoblastoma protein (RB): contribution from the RB C pocket.
|
| |
Mol Cell Biol, 18,
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|
|
|
|
|
|
|
M.E.Garber,
P.Wei,
V.N.KewalRamani,
T.P.Mayall,
C.H.Herrmann,
A.P.Rice,
D.R.Littman,
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The interaction between HIV-1 Tat and human cyclin T1 requires zinc and a critical cysteine residue that is not conserved in the murine CycT1 protein.
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| |
Genes Dev, 12,
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|
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P.D.Adams,
and
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(1998).
Negative control elements of the cell cycle in human tumors.
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| |
Curr Opin Cell Biol, 10,
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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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