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582 a.a.
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388 a.a.
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308 a.a.
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* Residue conservation analysis
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PDB id:
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Hydrolase/hydrolase inhibitor
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Title:
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Structure of the protein phosphatase 2a holoenzyme
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Structure:
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Protein phosphatase 2, regulatory subunit a (pr 65), alpha isoform. Chain: a, d. Fragment: scaffolding subunit. Synonym: protein phosphatase 2a. Engineered: yes. Serine/threonine-protein phosphatase 2a 56 kda regulatory subunit gamma isoform. Chain: b, e.
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Gene: ppp2r1a. Expressed in: escherichia coli. Expression_system_taxid: 469008. Gene: ppp2r5c, kiaa0044. Gene: ppp2ca. Expressed in: spodoptera frugiperda.
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Biol. unit:
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Tetramer (from
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Resolution:
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3.30Å
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R-factor:
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0.255
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R-free:
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0.299
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Authors:
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Y.Xu,Y.Chen,Y.Xing,Y.Chao,Y.Shi
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Key ref:
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Y.Xu
et al.
(2006).
Structure of the protein phosphatase 2A holoenzyme.
Cell,
127,
1239-1251.
PubMed id:
DOI:
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Date:
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28-Oct-06
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Release date:
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12-Dec-06
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PROCHECK
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Headers
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References
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P30153
(2AAA_HUMAN) -
Serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A alpha isoform from Homo sapiens
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Seq:
Struc:
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589 a.a.
582 a.a.
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Enzyme class:
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Chains C, F:
E.C.3.1.3.16
- protein-serine/threonine phosphatase.
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Reaction:
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1.
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O-phospho-L-seryl-[protein] + H2O = L-seryl-[protein] + phosphate
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2.
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O-phospho-L-threonyl-[protein] + H2O = L-threonyl-[protein] + phosphate
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O-phospho-L-seryl-[protein]
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+
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H2O
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=
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L-seryl-[protein]
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+
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phosphate
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O-phospho-L-threonyl-[protein]
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+
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H2O
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=
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L-threonyl-[protein]
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+
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phosphate
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Molecule diagrams generated from .mol files obtained from the
KEGG ftp site
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DOI no:
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Cell
127:1239-1251
(2006)
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PubMed id:
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Structure of the protein phosphatase 2A holoenzyme.
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Y.Xu,
Y.Xing,
Y.Chen,
Y.Chao,
Z.Lin,
E.Fan,
J.W.Yu,
S.Strack,
P.D.Jeffrey,
Y.Shi.
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ABSTRACT
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Protein Phosphatase 2A (PP2A) plays an essential role in many aspects of
cellular physiology. The PP2A holoenzyme consists of a heterodimeric core
enzyme, which comprises a scaffolding subunit and a catalytic subunit, and a
variable regulatory subunit. Here we report the crystal structure of the
heterotrimeric PP2A holoenzyme involving the regulatory subunit B'/B56/PR61.
Surprisingly, the B'/PR61 subunit has a HEAT-like (huntingtin-elongation-A
subunit-TOR-like) repeat structure, similar to that of the scaffolding subunit.
The regulatory B'/B56/PR61 subunit simultaneously interacts with the catalytic
subunit as well as the conserved ridge of the scaffolding subunit. The
carboxyterminus of the catalytic subunit recognizes a surface groove at the
interface between the B'/B56/PR61 subunit and the scaffolding subunit. Compared
to the scaffolding subunit in the PP2A core enzyme, formation of the holoenzyme
forces the scaffolding subunit to undergo pronounced conformational
rearrangements. This structure reveals significant ramifications for
understanding the function and regulation of PP2A.
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Selected figure(s)
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Figure 1.
Figure 1. Overall Structure of the Heterotrimeric PP2A
Holoenzyme Bound to Microcystin-LR (MCLR)
(A) Overall
structure of the PP2A holoenzyme bound to MCLR. The scaffolding
(Aα), catalytic (Cα), and regulatory B′/PR61 (B′-γ1)
subunits are shown in green, blue, and yellow, respectively.
MCLR is shown in magenta. B′-γ1 interacts with both Aα and
Cα through extensive interfaces. Cα interacts with Aα as
described (Xing et al., 2006). Three views are shown here to
reveal the essential features of the holoenzyme. Surprisingly,
B′-γ1 adopts a structure that closely resembles that of the
scaffolding subunit (discussed in detail later).
(B) A
surface representation of the PP2A holoenzyme. Aα and B′-γ1
are shown in surface representation. Cα is shown in backbone
worm to highlight the observation that the carboxyl terminus of
Cα binds to a surface groove at the interface between Aα and
B′-γ1. Figures 1A, 2A, 4A, and 4E were prepared using GRASP
(Nicholls et al., 1991); all other structural figures were made
using MOLSCRIPT (Kraulis, 1991).
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Figure 4.
Figure 4. Interactions among the Three Components of the PP2A
Holoenzyme
(A) A surface potential representation of the
PP2A holoenzyme. The electrostatic surface potential is shown
for Aα and B′-γ1. Note the acidic environment at the
interface between Aα and B′-γ1. The carboxyl terminus of Cα
extends out into a negatively charged surface groove at the
interface between Aα and B′-γ1. Two areas are circled. Area
1 involves a protein interface between Cα and B′-γ1. Area 2
centers on the recognition of the carboxyl terminus of Cα by
Aα and B′-γ1.
(B) A stereo view of the atomic
interactions between Cα and B′-γ1 in area 1. This interface
involves the HEAT-like repeats 6–8 of B′-γ1 and the α5
helix region of Cα. Side chains are colored orange. This
interface contains a number of hydrogen bonds, which are
represented by red dashed lines.
(C) A stereo view of the
recognition of the carboxyl terminus of Cα by Aα and B′-γ1
in area 2. This interface involves the HEAT-like repeats 5 and 6
of B′-γ1 and HEAT repeats 1 and 2 of Aα. Most residues from
the carboxyl terminus of Cα participate in specific
interactions. There is a good mixture of hydrogen bonds and van
der Waals interactions at this interface.
(D) Additional
interactions with Cα are provided by the extended loop within
HEAT-like motif 2 of B′-γ1.
(E) A surface representation
of the PP2A holoenzyme to highlight the binding mode of the
regulatory B′/PR61 subunit. Note that B′-γ1 uses its convex
surface to interact with the conserved ridge of Aα.
(F) A
stereo view of the atomic interactions between Aα and B′-γ1.
This interface is rich in van der Waals interactions and
involves six HEAT repeats of Aα.
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The above figures are
reprinted
by permission from Cell Press:
Cell
(2006,
127,
1239-1251)
copyright 2006.
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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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A.C.Eitelhuber,
S.Warth,
G.Schimmack,
M.Düwel,
K.Hadian,
K.Demski,
W.Beisker,
H.Shinohara,
T.Kurosaki,
V.Heissmeyer,
and
D.Krappmann
(2011).
Dephosphorylation of Carma1 by PP2A negatively regulates T-cell activation.
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EMBO J,
30,
594-605.
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D.Kitagawa,
I.Flückiger,
J.Polanowska,
D.Keller,
J.Reboul,
and
P.Gönczy
(2011).
PP2A phosphatase acts upon SAS-5 to ensure centriole formation in C. elegans embryos.
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Dev Cell,
20,
550-562.
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E.A.Foley,
M.Maldonado,
and
T.M.Kapoor
(2011).
Formation of stable attachments between kinetochores and microtubules depends on the B56-PP2A phosphatase.
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Nat Cell Biol,
13,
1265-1271.
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I.Cristóbal,
L.Garcia-Orti,
C.Cirauqui,
M.M.Alonso,
M.J.Calasanz,
and
M.D.Odero
(2011).
PP2A impaired activity is a common event in acute myeloid leukemia and its activation by forskolin has a potent anti-leukemic effect.
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Leukemia,
25,
606-614.
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J.T.Rodgers,
R.O.Vogel,
and
P.Puigserver
(2011).
Clk2 and B56β mediate insulin-regulated assembly of the PP2A phosphatase holoenzyme complex on Akt.
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Mol Cell,
41,
471-479.
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M.K.McConechy,
M.S.Anglesio,
S.E.Kalloger,
W.Yang,
J.Senz,
C.Chow,
A.Heravi-Moussavi,
G.B.Morin,
A.M.Mes-Masson,
M.S.Carey,
J.N.McAlpine,
J.S.Kwon,
L.M.Prentice,
N.Boyd,
S.P.Shah,
C.B.Gilks,
and
D.G.Huntsman
(2011).
Subtype-specific mutation of PPP2R1A in endometrial and ovarian carcinomas.
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J Pathol,
223,
567-573.
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S.J.Norwood,
D.J.Shaw,
N.P.Cowieson,
D.J.Owen,
R.D.Teasdale,
and
B.M.Collins
(2011).
Assembly and solution structure of the core retromer protein complex.
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Traffic,
12,
56-71.
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PDB codes:
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S.R.Pereira,
V.M.Vasconcelos,
and
A.Antunes
(2011).
The phosphoprotein phosphatase family of Ser/Thr phosphatases as principal targets of naturally occurring toxins.
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Crit Rev Toxicol,
41,
83.
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A.Grinthal,
I.Adamovic,
B.Weiner,
M.Karplus,
and
N.Kleckner
(2010).
PR65, the HEAT-repeat scaffold of phosphatase PP2A, is an elastic connector that links force and catalysis.
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Proc Natl Acad Sci U S A,
107,
2467-2472.
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A.K.Freeman,
V.Dapic,
and
A.N.Monteiro
(2010).
Negative regulation of CHK2 activity by protein phosphatase 2A is modulated by DNA damage.
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Cell Cycle,
9,
736-747.
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A.Saraf,
E.A.Oberg,
and
S.Strack
(2010).
Molecular determinants for PP2A substrate specificity: charged residues mediate dephosphorylation of tyrosine hydroxylase by the PP2A/B' regulatory subunit.
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Biochemistry,
49,
986-995.
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C.U.Stirnimann,
E.Petsalaki,
R.B.Russell,
and
C.W.Müller
(2010).
WD40 proteins propel cellular networks.
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Trends Biochem Sci,
35,
565-574.
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G.P.Shouse,
Y.Nobumori,
and
X.Liu
(2010).
A B56gamma mutation in lung cancer disrupts the p53-dependent tumor-suppressor function of protein phosphatase 2A.
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Oncogene,
29,
3933-3941.
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I.S.Seong,
J.M.Woda,
J.J.Song,
A.Lloret,
P.D.Abeyrathne,
C.J.Woo,
G.Gregory,
J.M.Lee,
V.C.Wheeler,
T.Walz,
R.E.Kingston,
J.F.Gusella,
R.A.Conlon,
and
M.E.Macdonald
(2010).
Huntingtin facilitates polycomb repressive complex 2.
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Hum Mol Genet,
19,
573-583.
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J.L.McConnell,
G.R.Watkins,
S.E.Soss,
H.S.Franz,
L.R.McCorvey,
B.W.Spiller,
W.J.Chazin,
and
B.E.Wadzinski
(2010).
Alpha4 is a ubiquitin-binding protein that regulates protein serine/threonine phosphatase 2A ubiquitination.
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Biochemistry,
49,
1713-1718.
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P.J.Khandelwal,
S.B.Dumanis,
L.R.Feng,
K.Maguire-Zeiss,
G.Rebeck,
H.A.Lashuel,
and
C.E.Moussa
(2010).
Parkinson-related parkin reduces α-Synuclein phosphorylation in a gene transfer model.
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Mol Neurodegener,
5,
47.
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S.Finnegan,
A.M.Mackey,
and
T.G.Cotter
(2010).
A stress survival response in retinal cells mediated through inhibition of the serine/threonine phosphatase PP2A.
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Eur J Neurosci,
32,
322-334.
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E.Kunttas-Tatli,
A.Bose,
B.Kahali,
C.P.Bishop,
and
A.P.Bidwai
(2009).
Functional dissection of Timekeeper (Tik) implicates opposite roles for CK2 and PP2A during Drosophila neurogenesis.
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Genesis,
47,
647-658.
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F.Kippert,
and
D.L.Gerloff
(2009).
Highly sensitive detection of individual HEAT and ARM repeats with HHpred and COACH.
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PLoS One,
4,
e7148.
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H.Fu,
H.Ma,
C.Zheng,
J.Lü,
X.Yu,
C.Li,
Y.Peng,
G.Liao,
W.Liu,
Y.Xiao,
Y.Liu,
and
D.W.Li
(2009).
Molecular cloning and differential expression patterns of the regulatory subunit B' gene of PP2A in goldfish, Carassius auratus.
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Sci China C Life Sci,
52,
724-732.
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H.G.Chen,
W.J.Han,
M.Deng,
J.Qin,
D.Yuan,
J.P.Liu,
L.Xiao,
L.Gong,
S.Liang,
J.Zhang,
Y.Liu,
and
D.W.Li
(2009).
Transcriptional regulation of PP2A-A alpha is mediated by multiple factors including AP-2alpha, CREB, ETS-1, and SP-1.
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PLoS One,
4,
e7019.
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H.L.Ma,
Y.L.Peng,
L.Gong,
W.B.Liu,
S.Sun,
J.Liu,
C.B.Zheng,
H.Fu,
D.Yuan,
J.Zhao,
P.C.Chen,
S.S.Xie,
X.M.Zeng,
Y.M.Xiao,
Y.Liu,
and
D.W.Li
(2009).
The Goldfish SG2NA Gene Encodes Two alpha-Type Regulatory Subunits for PP-2A and Displays Distinct Developmental Expression Pattern.
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Gene Regul Syst Bio,
3,
115-129.
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J.Guergnon,
U.Derewenda,
J.R.Edelson,
and
D.L.Brautigan
(2009).
Mapping of protein phosphatase-6 association with its SAPS domain regulatory subunit using a model of helical repeats.
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BMC Biochem,
10,
24.
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M.Goudreault,
L.M.D'Ambrosio,
M.J.Kean,
M.J.Mullin,
B.G.Larsen,
A.Sanchez,
S.Chaudhry,
G.I.Chen,
F.Sicheri,
A.I.Nesvizhskii,
R.Aebersold,
B.Raught,
and
A.C.Gingras
(2009).
A PP2A phosphatase high density interaction network identifies a novel striatin-interacting phosphatase and kinase complex linked to the cerebral cavernous malformation 3 (CCM3) protein.
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Mol Cell Proteomics,
8,
157-171.
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M.J.Van Kanegan,
and
S.Strack
(2009).
The protein phosphatase 2A regulatory subunits B'beta and B'delta mediate sustained TrkA neurotrophin receptor autophosphorylation and neuronal differentiation.
|
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Mol Cell Biol,
29,
662-674.
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M.Kong,
D.Ditsworth,
T.Lindsten,
and
C.B.Thompson
(2009).
Alpha4 is an essential regulator of PP2A phosphatase activity.
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Mol Cell,
36,
51-60.
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M.S.Kelker,
R.Page,
and
W.Peti
(2009).
Crystal structures of protein phosphatase-1 bound to nodularin-R and tautomycin: a novel scaffold for structure-based drug design of serine/threonine phosphatase inhibitors.
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J Mol Biol,
385,
11-21.
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PDB codes:
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P.Matre,
C.Meyer,
and
C.Lillo
(2009).
Diversity in subcellular targeting of the PP2A B'eta subfamily members.
|
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Planta,
230,
935-945.
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S.A.Kennedy,
M.L.Frazier,
M.Steiniger,
A.M.Mast,
W.F.Marzluff,
and
M.R.Redinbo
(2009).
Crystal structure of the HEAT domain from the Pre-mRNA processing factor Symplekin.
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J Mol Biol,
392,
115-128.
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PDB code:
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S.G.Brohawn,
J.R.Partridge,
J.R.Whittle,
and
T.U.Schwartz
(2009).
The nuclear pore complex has entered the atomic age.
|
| |
Structure,
17,
1156-1168.
|
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|
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|
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S.Li,
C.Brignole,
R.Marcellus,
S.Thirlwell,
O.Binda,
M.J.McQuoid,
D.Ashby,
H.Chan,
Z.Zhang,
M.J.Miron,
D.C.Pallas,
and
P.E.Branton
(2009).
The adenovirus E4orf4 protein induces G2/M arrest and cell death by blocking protein phosphatase 2A activity regulated by the B55 subunit.
|
| |
J Virol,
83,
8340-8352.
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S.M.País,
M.A.González,
M.T.Téllez-Iñón,
and
D.A.Capiati
(2009).
Characterization of potato (Solanum tuberosum) and tomato (Solanum lycopersicum) protein phosphatases type 2A catalytic subunits and their involvement in stress responses.
|
| |
Planta,
230,
13-25.
|
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T.Glatter,
A.Wepf,
R.Aebersold,
and
M.Gstaiger
(2009).
An integrated workflow for charting the human interaction proteome: insights into the PP2A system.
|
| |
Mol Syst Biol,
5,
237.
|
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Y.Shi
(2009).
Assembly and structure of protein phosphatase 2A.
|
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Sci China C Life Sci,
52,
135-146.
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Y.Shi
(2009).
Serine/threonine phosphatases: mechanism through structure.
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Cell,
139,
468-484.
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Z.Li,
and
J.B.Stock
(2009).
Protein carboxyl methylation and the biochemistry of memory.
|
| |
Biol Chem,
390,
1087-1096.
|
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Z.Xu,
B.Cetin,
M.Anger,
U.S.Cho,
W.Helmhart,
K.Nasmyth,
and
W.Xu
(2009).
Structure and function of the PP2A-shugoshin interaction.
|
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Mol Cell,
35,
426-441.
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PDB code:
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A.A.Sablina,
and
W.C.Hahn
(2008).
SV40 small T antigen and PP2A phosphatase in cell transformation.
|
| |
Cancer Metastasis Rev,
27,
137-146.
|
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B.Wang,
P.Zhang,
and
Q.Wei
(2008).
Recent progress on the structure of Ser/Thr protein phosphatases.
|
| |
Sci China C Life Sci,
51,
487-494.
|
|
|
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C.E.Zhang,
Q.Tian,
W.Wei,
J.H.Peng,
G.P.Liu,
X.W.Zhou,
Q.Wang,
D.W.Wang,
and
J.Z.Wang
(2008).
Homocysteine induces tau phosphorylation by inactivating protein phosphatase 2A in rat hippocampus.
|
| |
Neurobiol Aging,
29,
1654-1665.
|
|
|
|
|
|
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C.de Chiara,
R.P.Menon,
and
A.Pastore
(2008).
Structural bases for recognition of Anp32/LANP proteins.
|
| |
FEBS J,
275,
2548-2560.
|
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PDB code:
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D.L.Lizotte,
J.J.Blakeslee,
A.Siryaporn,
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PP2A-dependent disruption of centrosome replication and cytoskeleton organization in Drosophila by SV40 small tumor antigen.
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Differential expression of the catalytic subunits for PP-1 and PP-2A and the regulatory subunits for PP-2A in mouse eye.
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Mol Vis,
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PDB codes:
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PDB code:
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PDB code:
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The B''/PR72 subunit mediates Ca2+-dependent dephosphorylation of DARPP-32 by protein phosphatase 2A.
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PDB codes:
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U.S.Cho,
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PDB code:
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|
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|
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|
|
Y.Chen,
Y.Xu,
Q.Bao,
Y.Xing,
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Nat Struct Mol Biol,
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PDB code:
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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
codes are
shown on the right.
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