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PDBsum entry 1ol6
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Contents |
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* Residue conservation analysis
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References listed in PDB file
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Key reference
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Title
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Structural basis of aurora-A activation by tpx2 at the mitotic spindle.
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Authors
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R.Bayliss,
T.Sardon,
I.Vernos,
E.Conti.
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Ref.
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Mol Cell, 2003,
12,
851-862.
[DOI no: ]
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PubMed id
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Abstract
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Aurora-A is an oncogenic kinase essential for mitotic spindle assembly. It is
activated by phosphorylation and by the microtubule-associated protein TPX2,
which also localizes the kinase to spindle microtubules. We have uncovered the
molecular mechanism of Aurora-A activation by determining crystal structures of
its phosphorylated form both with and without a 43 residue long domain of TPX2
that we identified as fully functional for kinase activation and protection from
dephosphorylation. In the absence of TPX2, the Aurora-A activation segment is in
an inactive conformation, with the crucial phosphothreonine exposed and
accessible for deactivation. Binding of TPX2 triggers no global conformational
changes in the kinase but pulls on the activation segment, swinging the
phosphothreonine into a buried position and locking the active conformation. The
recognition between Aurora-A and TPX2 resembles that between the cAPK catalytic
core and its flanking regions, suggesting this molecular mechanism may be a
recurring theme in kinase regulation.
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Figure 3.
Figure 3. Structure of Aurora-A Bound to TPX2(A) View of
the complex between the catalytic domain of human Aurora
(AuroraΔN, yellow) and the N-terminal domain of TPX2 shown in
typical kinase orientation. An upstream stretch of TPX2 (red)
binds at the N-terminal lobe of Aurora-A, and a downstream
stretch (pink) binds between the two lobes. A dotted line in
pink marks the approximate path of the linker connecting the two
TPX2 stretches (disordered and not modeled).(B) View of the
complex after a 180° rotation about the vertical axis in
respect to view in (A) shows more clearly the two stretches of
TPX2 binding to Aurora-A.(C) The upstream stretch of TPX2 (red,
residues 7–21^TPX) binds at a hydrophobic surface groove
present in the N-terminal lobe of the kinase (gray cartoon,
yellow side chains). Details of the extensive interactions are
shown in the same orientation as in (B). Aurora-A residues are
labeled in black, and TPX2 residue labels are color coded as the
structure.(D) The downstream helical stretch of TPX2 (pink,
residues 30–43^TPX) binds Aurora-A near helix αC and the
activation segment, close to but not directly in contact with
phospho-Thr288^AUR (green). Details of interactions are shown in
the same orientation as in (B) and (C).
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Figure 5.
Figure 5. TPX2-Aurora-A Intermolecular Interactions
Resemble cAPK Intramolecular Interactions(A and B) Transparent
surfaces representing the conserved catalytic cores of (A)
Aurora-A and (B) cAPK show similar surface grooves in the
N-terminal lobe (between helix αC and the β sheet, gray
cartoon) and a similar pocket between the two lobes (formed by
the activation segment and helix αC, gray cartoon). The
portions of TPX2 binding to Aurora-A are shown in red and pink
(A), and the N- and C-terminal extensions to the cAPK catalytic
core are shown in light blue (B).(C and D) Schematic diagram of
the intermolecular interactions between Aurora-A and TPX2 (pink
and red) and of the cAPK intramolecular interactions (light
blue) shows that their mode of recognition at the atomic level
is rather similar. The hydrophobic interactions of Tyr8^TPX,
Tyr10^TPX, Trp34^TPX, and Phe35^TPX are recapitulated by
Phe347^cAPK, Phe350^cAPK, Trp30^cAPK, and Phe26^cAPK.
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The above figures are
reprinted
by permission from Cell Press:
Mol Cell
(2003,
12,
851-862)
copyright 2003.
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