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PDBsum entry 2nyl
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Hydrolase/hydrolase inhibitor
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PDB id
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2nyl
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Contents |
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582 a.a.
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388 a.a.
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293 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 the protein phosphatase 2a holoenzyme.
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Authors
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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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Ref.
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Cell, 2006,
127,
1239-1251.
[DOI no: ]
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PubMed id
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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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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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