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PDBsum entry 3dw8
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Hydrolase/hydrolase inhibitor
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PDB id
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3dw8
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Contents |
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582 a.a.
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421 a.a.
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288 a.a.
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References listed in PDB file
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Key reference
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Title
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Structure of a protein phosphatase 2a holoenzyme: insights into b55-Mediated tau dephosphorylation.
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Authors
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Y.Xu,
Y.Chen,
P.Zhang,
P.D.Jeffrey,
Y.Shi.
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Ref.
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Mol Cell, 2008,
31,
873-885.
[DOI no: ]
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PubMed id
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Abstract
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Protein phosphatase 2A (PP2A) regulates many essential aspects of cellular
physiology. Members of the regulatory B/B55/PR55 family are thought to play a
key role in the dephosphorylation of Tau, whose hyperphosphorylation contributes
to Alzheimer's disease. The underlying mechanisms of the PP2A-Tau connection
remain largely enigmatic. Here, we report the complete reconstitution of a Tau
dephosphorylation assay and the crystal structure of a heterotrimeric PP2A
holoenzyme involving the regulatory subunit Balpha. We show that Balpha
specifically and markedly facilitates dephosphorylation of the phosphorylated
Tau in our reconstituted assay. The Balpha subunit comprises a seven-bladed beta
propeller, with an acidic, substrate-binding groove located in the center of the
propeller. The beta propeller latches onto the ridge of the PP2A scaffold
subunit with the help of a protruding beta hairpin arm. Structure-guided
mutagenesis studies revealed the underpinnings of PP2A-mediated
dephosphorylation of Tau.
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Figure 2.
Figure 2. Overall Structure of the Heterotrimeric PP2A
Holoenzyme Involving the Bα Subunit
(A) Overall structure
of the PP2A holoenzyme involving the Bα subunit and bound to
MCLR. The scaffold (Aα), catalytic (Cα), and regulatory B
(Bα) subunits are shown in yellow, green, and blue,
respectively. MCLR is shown in magenta. Bα primarily interacts
with Aα through an extensive interface. Cα interacts with Aα
as described (Xing et al., 2006). Two views are shown here to
reveal the essential features of the holoenzyme.
(B) The
regulatory Bα subunit contains a highly acidic top face and a
hairpin arm. The electrostatic surface potential of Bα is
shown. Aα and Cα are shown in backbone worm.
(C)
Comparison of the distinct conformations of the A subunit in the
PP2A core enzyme and in the two holoenzymes. Figures 2B, 3C, and
5C 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. Specific Recognition of the B Subunit for the PP2A
Scaffold Subunit
(A) A stereo view of the atomic
interactions between the β2C-β2D hairpin arm of Bα and HEAT
repeats 1 and 2 of Aα. This interface is dominated by van der
Walls contacts.
(B) A stereo view of the recognition
between the bottom face of Bα and HEAT repeats 3–7. This
interface contains a number of hydrogen bonds, which are
represented by red dashed lines.
(C) Structural comparison
of the PP2A holoenzymes involving the regulatory B/B55/PR55 and
B′/B56/PR61 subunits.
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The above figures are
reprinted
by permission from Cell Press:
Mol Cell
(2008,
31,
873-885)
copyright 2008.
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